Restless leg syndrome or overactive nerve treatment

ABSTRACT

Restless Leg Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) can be treated using high frequency (HF) electrostimulation. This can include selecting or receiving a subject presenting with RLS or PLMD. At least one electrostimulation electrode can be located at a location associated with at least one of, or at least one branch of, a sural nerve, a peroneal nerve, or a femoral nerve. HF electrostimulation can be delivered to the subject, which can include delivering subsensory, subthreshold, AC electrostimulation at a frequency that exceeds 500 Hz and is less than 15,000 Hz to the location to help reduce or alleviate the one or more symptoms associated with RLS or PLMD. A charge-balanced controlled-current HF electrostimulation waveform can be used.

CLAIM OF PRIORITY

This patent application is a continuation of International ApplicationNumber PCT/US2018/012631 filed Jan. 5, 2018, which claims the benefit ofpriority of: (1) Shriram Raghunathan U.S. Provisional Patent ApplicationNo. 62/442,798, entitled “METHODS TO TREAT SYMPTOMS FROM OVERACTIVITY OFNERVES,” filed on 5 Jan. 2017; and (2) Shriram Raghunathan U.S.Provisional Patent Application No. 62/552,690, entitled “SYSTEMS METHODSAND DEVICES TO MODULATE NERVE ACTIVITY TO TREAT NEUROLOGICAL DISORDERAND IMPROVE SLEEP QUALITY,” filed on 31 Aug. 2017; each of which areincorporated by reference herein in their entirety and the benefit ofpriority of each of which is claimed.

TECHNICAL FIELD

This document pertains generally, but not by way of limitation, tomedical diagnostic and treatment devices and methods, and moreparticularly, but not by way of limitation to Restless Legs Syndrome(RLS) or overactive nerve treatment.

BACKGROUND

Certain neurological disorders with bothersome symptoms can beattributed to overactivity of sensory or other peripheral nerve fibers,which can disrupt quality of life. In particular, Restless Legs Syndrome(RLS) and Periodic Leg Movement Disorder (PLMD) are two suchneurological conditions that can significantly affect sleep in humanpatients. RLS (which can also be called Willis-Ekbom Disease (WED))patients can experience uncomfortable tingling sensations in their lowerlimbs (legs). Such sensations can often be immediately relieved bymoving the limb voluntarily, but doing so can interfere with the RLSpatient's ability to fall asleep. PLMD patients can experiencespontaneous movements of the lower legs during periods of sleep. Thiscan cause the PLMD patient to wake up.

Burbank et al. U.S. Pat. No. 9,017,273, which issued on Apr. 27, 2015,is directed to devices and methods for treating restless legs syndrome,such as by providing a mechanical counterstimulation vibration having afrequency of between 50 Hz and 10 per minute.

Elborno U.S. Patent Publication 2015/0066105, which published on Mar. 5,2015, is directed to devices and methods for treating essential tremoror restless leg syndrome using spinal cord stimulation.

Kent U.S. Patent Publication 2016/0354604, which published on Dec. 8,2016, is directed to a method and apparatus for treating restless legssyndrome using stimulation of a sacral or lumbar region of the patient.

Matsen U.S. Pat. No. 8,938,303, which issued on Jan. 20, 2015, isdirected to a restless leg therapeutic device, such as using a 25 Voltelectricity generator to repeatedly cause constant muscle contractions.(See Matsen U.S. Pat. No. 8,938,303 at col. 6, lines 17-47.)

Lozano U.S. Pat. No. 7,774,068, which issued on Aug. 10, 2010, isdirected to a system and method for treating movement disorders,including restless leg syndrome, such as using cortical brainstimulation.

For a patient diagnosed with primary RLS (e.g., RLS that is notsecondary to some other primary co-morbidity, such as diabetes,neuropathy, etc., that may itself be separately treatable, in somecases), the first line of treatment may involve one or more of behaviorchanges, sleep changes, or exercise. The second line of treatment mayinvolve dopaminergic therapy or iron level management, or both. Thethird line of treatment may involve one or more of anti-convulsants,off-label opiates, or benzodiazepines. In sum, the current treatmentsfor RLS patients predominantly include pharmaceutical therapies, whichcan have serious side-effects.

SUMMARY

The present inventor has recognized that Restless Legs Syndrome (RLS) orPeriodic Limb Movement Disorder (PLMD) can be treated using highfrequency (HF) electrostimulation. This can include selecting orreceiving a subject presenting with RLS or PLMD. At least oneelectrostimulation electrode can be located at a location associatedwith at least one of, or at least one branch of, a sural nerve, aperoneal nerve, or a femoral nerve. HF electrostimulation can bedelivered to the subject, which can include delivering subsensory,subthreshold, alternating current (AC) electrostimulation at a frequencythat exceeds 500 Hz and is less than 15,000 Hz to the location to helpreduce or alleviate the one or more symptoms associated with RLS orPLMD. A charge-balanced controlled-current HF electrostimulationwaveform can be used. The HF electrostimulation can be configured to becarried out without increasing blood flow to adjacent tissue.

The present inventor has discovered that, among other things, the HFsubsensory and subthreshold electrostimulation waveform and techniquesdescribed herein can work better than low frequency transcutaneouselectrical neurostimulation (TENS)—which can be sensed by the RLSpatient, and which can actually make the RLS patient's symptoms moreuncomfortable.

This Summary is intended to provide an overview of subject matter of thepresent patent application. It is not intended to provide an exclusiveor exhaustive explanation of the invention. The Detailed Description isincluded to provide further information about the present patentapplication.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsmay describe similar components in different views. Like numerals havingdifferent letter suffixes may represent different instances of similarcomponents. The drawings illustrate generally, by way of example, butnot by way of limitation, various embodiments discussed in the presentdocument.

FIG. 1A illustrates an example of an ankle and foot region of a lowerlimb of a restless legs syndrome (RLS) patient, showing a targetedportion that can include a sural nerve or one or more of its branches.

FIG. 1B illustrates an example of a wearable external electrostimulationdevice shown located in close proximity to the targeted sural nerve orits branches.

FIG. 1C illustrates an example of the wearable externalelectrostimulation device shown located in close proximity to a targetedregion of a targeted peroneal nerve.

FIG. 1D illustrates an example showing how the wearable externalelectrostimulation device can be located in close proximity to atargeted region of a targeted femoral nerve.

FIG. 2 shows an example of a particular mechanism of action that can bespecifically targeted by delivering a tailored electrostimulation, suchas described herein, such as to a specifically targeted location.

FIG. 3 shows an example of experimental Suggested Immobilization Test(SIT) data from a patient with severe RLS, who was on medications,“baseline” SIT data (without electrostimulation) and with “therapy” SITdata (with applied stimulation).

FIG. 4 shows an example summarizing SIT data results “before” and“after” electrostimulation of the superficial peroneal nerve target ofsix additional patients.

FIG. 5 shows an example of SIT data from a patient study in which aBurst sensory low-frequency (LF) TENS electrostimulation waveform wasturned, then switching directly to a subsensory high-frequency (HF)electrostimulation waveform.

FIG. 6 illustrates conceptually an example of a resulting compoundaction potential (CAP) and the contribution of each nerve fibersub-type, which can be sensed and recorded at a distance away from theapplied electrostimulation.

FIG. 7 illustrates a conceptual example of how each individual nervefiber component may be detected.

FIG. 8 illustrates a conceptual example of three different recordingelectrode waveforms, such as for comparing preferential andnon-preferential recruitment or activation of a specific nerve fibertype, such as within a target nerve.

FIG. 9A shows an example of SIT data in which HF electrostimulation wasturned on, then off, yielding suppression then resumption of RLSsymptoms.

FIG. 9B shows an example of electrostimulation sensory comparative datafor typical low frequency (LF) transcutaneous electricalneurostimulation waveforms as compared to a (HF) transcutaneouselectrostimulation waveform according to the present techniques.

FIG. 9C shows calculated charge injection comparing the present HFwaveforms with typical LF TENs waveforms.

FIG. 9D shows a conceptualized (not real data) example of such a FlexionReflex (Fr) response to a test electrostimulation stimulus.

FIG. 9E shows a conceptualized (not real data) example of such FlexionReflex Response amplitude to a test electrostimulation stimulus in thepresence of a HF electrostimulation applied at a peripheral nerve,indicating a result of the inhibitory cascade of neural activationdescribed in FIG. 2.

FIG. 10 shows an example of an open-loop RLS electrostimulationtreatment system.

FIG. 11A shows an example of a closed-loop RLS electrostimulationtreatment system.

FIG. 11B shows an example of a block diagram of portions of an RLSelectrostimulation system, such as can be configured to produce acontrolled-current waveform, such as including when a variable loadimpedance is present.

FIG. 11C is a flow chart showing generally an example of portions of aoperating method, such as can be performed using the RLSelectrostimulation system.

FIG. 12 shows an example of a technique for using one or more sensorcircuits or the user input device, or both, such as for controlling RLSelectrostimulation therapy delivery.

FIG. 13 shows an example of a technique, similar to the technique shownin and described with respect to FIG. 12, but modified to addressepisodes of leg twitching or motion occurring after the subject fallsasleep, such as can occur in periodic limb movement disorder (PLMD)patients.

FIG. 14 shows an example in which one or more of the open-loop RLSelectrostimulation systems or one or of the closed-loop RLSelectrostimulation systems, or both, can be communicatively coupled to aremote server such as via a cloud or communication network.

FIG. 15 includes an example of a stabilizer, such as to carry or holdall or portions of an RLS electrostimulation system in place.

FIG. 16A shows a multilayer example of various layers of the disposableor other detachable patch, such as shown in FIG. 15 in use with the kneesleeve.

FIG. 16B shows an example of portions of a stabilizer, such as caninclude a multi-layer disposable or other detachable patch, such as canbe separately attachable to an electronics unit.

FIG. 16C shows an example of placement of the detachable adhesive patchof FIG. 16B, such as at a peroneal nerve target location, just below theknee on an anterior portion of the lower limb, with a detachableelectronics unit.

FIG. 16D shows an example of portions of a stabilizer, such as caninclude a multi-layer disposable or other detachable patch, similar tothe patch shown in FIG. 16B, but shown with bilateral lobes, such as canprovide additional hydrogel electrode locations.

FIG. 16E shows an example of placement of the detachable adhesive patchof FIG. 16D, such as at a peroneal nerve target location, just below theknee on an anterior portion of the lower limb, with a detachableelectronics unit.

FIG. 16F shows an example of a local external interface device.

FIG. 16G shows an example of a block diagram of the local externalinterface device.

FIG. 17 illustrates an example of a transdermal chemical agent deliveryadhesive patch.

FIG. 18 shows an alternative closed-loop ultrasound embodiment, such ascan provide ultrasound energy to one or more of the target nervelocations described herein (e.g., femoral nerve, peroneal nerve, orsural nerve).

FIGS. 19A, 19B shows an example of a method of using the HF RLSelectrostimulation therapy described herein in conjunction withpharmaceutical therapy.

FIG. 20 shows an example of a technique that can be used to turn on andoff the HF RLS electrostimulation therapy such as described herein.

FIG. 21 shows an example a possible RLS electrostimulation waveform,such as can be generated by the present RLS electrostimulation therapysystem.

FIGS. 22 and 23 show examples of waveform patterns that are specificallyconfigured to inhibit or prevent short-term neural accommodation

FIG. 24 is a flow chart showing an example of a technique for usingflexion response information for establishing one or more RLSelectrostimulation parameters, either initially, or recurrently, such asto help avoid neural accommodation or to help maintain subsensorytherapy.

DETAILED DESCRIPTION

Restless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD)can be treated using high frequency (HF) electrostimulation. This caninclude selecting or receiving a subject presenting with RLS or PLMD. Atleast one electrostimulation electrode can be located at a locationassociated with at least one of, or at least one branch of, a suralnerve, a peroneal nerve, or a femoral nerve. HF electrostimulation canbe delivered to the subject, which can include delivering subsensory,subthreshold, AC electrostimulation at a frequency that exceeds 500 Hzand is less than 15,000 Hz to the location to help reduce or alleviatethe one or more symptoms associated with RLS or PLMD. A charge-balancedcontrolled-current HF electrostimulation waveform can be used.

Pathophysiology of RLS

RLS pharmaceutical treatments can include dopamine supplementation(e.g., levodopa), dopamine agonists (e.g., ropinirole, pramipexole), oranticonvulsants

(e.g., gabapentin), in certain cases. Mechanical vibration padapproaches are believed not efficacious or better than placebo. A largenumber of RLS patients can suffer from augmentation of the RLS disease,which is a side-effect of some RLS drugs, and which can cause symptomsof the RLS disease to no longer be in the lower limbs or confined toperiods of rest and sleep only. As a result, a number of these RLSaugmentation patients can end up on sleep medications or opiates tomanage their condition, with possible additional side-effects.

The underlying pathophysiology that causes people to develop RLS may behypothesized to involve a central dopamine deficiency. The dramatic andimmediate treatment benefits from levodopa may lead to a view that RLSpatients may have a significant brain dopamine deficiency. The search todocument the dopamine abnormalities in RLS is more difficult thanexpected and yields surprising results. Initial cerebrospinal fluid(CSF) analyses showed no differences between RLS patients and controlpatients for the major proteins related to dopamine. A repeat analysisof 3-orthymethyl dopamine (3-OMD) indicated significant increases withinthe CSF in 2 independent samples (See Allen, Connor, & Hyland, 2009).Moreover, the increases correlated with the dopamine metabolite,homovanillic acid (HVA). Given the metabolic pathways from tyrosinehydroxylase to dopamine, the increase in both 3-OMD and HVA may be bestexplained as an increase in tyrosine hydroxylase activity leading toincreased dopamine production.

A problem arises: if in the RLS patient's brain dopamine is alreadyabnormally increased, how does increasing this further by administeringlevodopa reduce the symptoms? Resolving this apparent contradiction mayinvolve recognizing that there is a strong circadian aspect of bothdopaminergic activity and

RLS symptoms. Increased dopaminergic stimulation can produce apostsynaptic downregulation, likely at both receptor and internalcellular function. A general pattern of decreased D2 receptors,especially for the more severe RLS cases, may represent part of thisdown-regulation of response. But dopamine has a clear circadian activitypattern, decreasing in the evening and night, and increasing in themorning. The RLS postsynaptic adjustment to increased dopaminestimulation may suffice for the daytime, but seems to overcompensatewhen dopamine levels arelower during the evening and night. This may produce a relative eveningand nighttime dopamine deficit, despite an overall dopamine increase.Thus, there is a circadian pattern of evening and night RLS symptomswith, if anything, hyperalertness and arousal in the morning that mayprevent the expected sleepiness for the short and disrupted RLS sleepepisode.

In sum, RLS pathophysiology can occur in a wide range of locations andsystems and may have multiple pathways to disease. Pathophysiologicfindings for RLS may help guide treatment advances for reducing the riskof dopamine augmentation and emphasizing the importance of developingbetter methods to manage RLS symptoms.

Pharmacological Treatments for RLS

Dopaminergic agents can be a first-line pharmacological therapy for RLS.Patients with serum ferritin values in the low-to-normal range maybenefit from iron supplementation, as may difficult-to-treat RLSpatients on dopaminergic treatment, in whom iron supplementation mayinhibit or reduce RLS augmentation (Trenkwalder & Paulus, 2010).

Dopaminergic therapy for RLS can include dopamine agonists, but levodopawas the first dopaminergic agent used for RLS. Dopamine agonists may besuperior to levodopa with respect to efficacy parameters, and less RLSaugmentation may occur with these drugs than with levodopa. However, thedopaminergic adverse-effect profile, which can include nausea, bloodpressure decrease, or dizziness, may be less severe with levodopa.Limitations of levodopa may lie both in its lack of efficacy and in RLSaugmentation, the latter of which occurred in 50-70% of RLS patients inlong-term observational studies. Table 1 below shows a list ofdopaminergic medications for RLS treatment.

TABLE 1 Dopaminergic medications for RLS treatment Medication Daily DoseRate Possible Side Effects Levodopa/dopa- 100/25-400/100 mg Diarrhea,nausea, decarboxylase inhibitor dyspepsia, reduced general drive, muscleweakness, somnolence, headache Pramipexole 0.125-0.75 mg Nausea,dizziness, fatigue, somnolence, headache, orthostatic hypotensionRopinirole 0.25-4 mg Nausea, dizziness, fatigue, somnolence, headache,orthostatic hypotension Rotigotine (transdermal 1-3 mg Nausea,dizziness, patches) fatigue, somnolence, headache, orthostatichypotension. Cabergoline 0.5-2.0 mg Nausea, dizziness, fatigue,somnolence, headache, orthostatic hypotension, cardiac valvular diseasePergolide 0.25-0.75 mg Nausea, dizziness fatigue, somnolence, headache,orthostatic hypotension, cardiac valvular disease

Electrostimulation Treatment of RLS

The present techniques can include electrostimulation treatment of RLSor PLMD. The present techniques can include one or more specifiedselected nerve targets, such as a sural nerve, a peroneal nerve, or afemoral nerve, which the present inventor has recognized to beparticularly useful electrostimulation target locations for RLS or PLMD.RLS symptoms are most commonly reported to originate in the lower legsfor most patients. Specifically, the RLS symptoms affect the anteriortibialis region in the front and the gastrocnemius muscle region in theback. Without being bound by theory, the overactivity of sensory nerveafferents emerging from these regions of innervation likely cause thesymptoms to go away temporarily when these muscles activate (e.g., whenthe leg is moved). The superficial peroneal nerve and its directperipherally extending branches and the sural nerve and its directperipherally extending branches are the primary sensory nervesinnervating this region of the leg. Therefore, such nerve locations areprime targets for RLS electrostimulation therapy.

In RLS or PLMD patients reporting symptoms that originate in the upperleg, the femoral nerve and its direct peripherally extending branchescarry most of the sensory innervation back from the rectus femorismuscle and the biceps femoris on the back of the leg. Therefore, thefemoral nerve provides an additional target location for RLSelectrostimulation.

Peroneal Nerve Location Example

At the peroneal nerve target location, at least one electrode can beplaced, such as preferably externally on the skin directly above or asclose to possible to the superficial peroneal nerve (FIG. 1C). At leastone electrode can be located directly below the bone landmark of thefibula in the outside of the knee below the lateral collateral ligament,or within 1 to 2 inches of the same. A second electrode may be locatedsuch that there is at least 1 inch of separation from the edge of thefirst electrode to the edge of the second electrode. The secondelectrode can be placed either along the length of the peroneal nerve,e.g., further down the leg, or the second electrode can be placeddirectly over the tibia, such as at about 1 to 2 inches below the firstelectrode. In an example, this second electrode can be located directlyopposing the first electrode, to the inside of the knee, directly belowthe medial collateral ligament on the side of the tibia. Theelectrostimulation field may then be varied, such as to extend between asmaller or longer distance, such as to decrease sensory perception bythe patient, if desired.

In an example, two separate or different electrostimulation fields canbe applied, such as by using the second electrode on the tibia as thecommon return electrode, such as can create a modulatedelectrostimulation field across the leg below the knee.

Sural Nerve Location

At the sural nerve location, at least one electrode can be placed, suchas preferably externally on the skin directly above, or as close topossible to the sural nerve, such as at a location between the lateralmalleolus and calcaneus on the outside of the subject's foot. As shownin FIG. 1B, multiple electrodes can be located along the length of aportion of the sural nerve, such as with one electrode that can belocated directly behind the 2 cm bony mass of the lateral malleolus. Oneor more additional electrodes can also be provided, such as can berespectively included on two extended “wings” that can be about 1.0 to1.5 inches laterally spread from the central electrode, such as can forma 90 degree to 180 degree angle with the central electrode, such as tolocate these additional electrodes along the length of the sural nerve,for example, a first additional electrode can be located at adjacent tothe calcaneal tendon and a second additional electrode can be locatedabove the base of the lateral longitudinal arch on the outside of thefoot.

Femoral Nerve Location

At the femoral nerve location, at least one electrode can be placed,such as preferably externally on the skin directly above, or as close topossible to the femoral nerve, such as at a location at the approximatecenter of the “femoral triangle” that is bordered by the inguinalligament on the superior side, the sartorius muscle on the lateral side,and the adductor longus on the medial side. In examples that can includemultiple electrodes, such additional electrodes may be located with aminimum of 1 inch separation to the first electrode, from electrode edgeto electrode edge, and can be arranged for placement along the length ofthe femoral nerve.

The present techniques can additionally or alternatively includeelectrostimulation that can be specially configured to preferentiallyactivate certain nerve fibers over others, such as to inhibit, treat,reduce, prevent, or avoid one or more RLS symptoms. Theelectrostimulation can be specially configured to be subsensory (e.g.,not noticeable enough to affect the patient's ability to fall asleep orstay asleep). The electrostimulation can be specially configured to besubthreshold (e.g., to avoid muscle activation in the patient, whichcould also interfere with the patient's ability to fall asleep or stayasleep). The electrostimulation can be configured very differently thantraditional low frequency sensory transcutaneous electrical nervestimulation (TENS), which can be ineffective or can even exacerbate RLSsymptoms, thereby worsening the RLS patient's ability to fall asleep.The present techniques can be applied in an open-loop fashion, can allowpatient control or titration, or can include closed-loop operation, suchas can be based upon one or more sensed or received physiologicalparameters, such as sleep-state, or the like.

FIG. 1A illustrates an example of an ankle and foot region of a lowerlimb of an RLS patient, showing a sural nerve 100 and its branches 102A,102B, 102C, such as can be specifically targeted by locating anelectrostimulation device in close proximity thereto, such as fordelivering an electrostimulation that can be configured to inhibit,reduce, or eliminate an RLS symptom.

FIG. 1B illustrates an example of a wearable external electrostimulationdevice 104 shown located in close proximity to the targeted sural nerve100 or its branches 102A-C, such as for delivering a transcutaneouselectrical stimulation thereto. In this example, the electrostimulationdevice 104, such as can include an adhesive patch 106, such as can carryan electronics unit 108 such as with separate or integrated electrodes110A-B that can be electrically connected to the electronics unit 108.FIG. 1B shows electrodes 110A-B located separately on the adhesive patch102 from the electronics unit 108, however, one or both of theelectrodes 110A-B (or an additional electrode 110C (not shown) can belocated on a patient-facing portion of the electronics unit 108, such ascan be left exposed to the patient's skin by an opening in the adhesivepatch 106. In an example, the electrostimulation device 104 can beadhered to or otherwise affixed or stabilized at a location on a lateralor medial surface of the foot, such as upon the posterolateral side ofthe leg near the dorsal aspect of the lateral side of the foot, such astoward the heel and behind and adjacent to a condylar surface of theankle.

FIG. 1C illustrates an example of the wearable externalelectrostimulation device 104 shown located in close proximity to atargeted region 103 of a targeted peroneal nerve, such as at an anterioror lateral location just below the subject's knee, such as over aportion of the deep peroneal nerve. The wearable externalelectrostimulation device 104 can be alternatively or additionallylocated at an even more inferiorly-located region on the lower leg, suchas over a portion of a superficial peroneal nerve, such as can innervateone or more parts of the tibialis anterior muscle.

FIG. 1D illustrates an example showing how the wearable externalelectrostimulation device can be located in close proximity to atargeted region 106 of a targeted femoral nerve, such as at an anteriorupper thigh region or above the knee at an anterior and slightly moremedial location.

At any of the desired target locations, the electrostimulation device104 can be additionally or alternatively localized using a wearablecomponent or garment, for example, such as with the electrostimulationdevice 104 carried by compression shorts or leggings, compression kneebrace, ankle brace, sock, legging, sleeve, or the like.

FIG. 2 shows an example of a particular mechanism of action that can bespecifically targeted by delivering a tailored electrostimulation, suchas described herein, such as to a specifically targeted location. But asan initial matter, it is worth noting that peripheral nerves are made upof a bundle of sub-types of nerves, such as can be classified as type A,B, or C, such as based on their respective conduction velocities anddiameter, such as summarized in Table 2.

TABLE 2 Nerve Fiber Types and Characteristics Type of DiameterConduction Nerve Fiber (micro- Velocity (Lloyd's) InformationMyelinated? meters) (m/s) A-alpha (or Proprioception Yes 13-20 80-120“Type I”) A-Beta (or Touch Yes  6-12 35-90  “Type II” A-Delta (or PainYes 1-5 5-40 “Type III”) (Mechanical and Thermal) C (or Pain No 0.2-.5 0.5-2   “Type IV”) (Mechanical, thermal, chemical)

The A-alpha and A-beta nerve fibers are some of the largest in diameter,and can be targeted and recruited by lower amplitudes ofelectrostimulation, and are some of the fastest conducting nerve fibers,as evidenced by their reported conduction velocities as summarized inTable 2.

Without being bound by theory, it is believed that alleviating RLSsymptomology can benefit from electrostimulation that can bespecifically tailored, such as to preferentially recruit one or moretypes of nerve fibers at the specifically targeted location, such asexplained with respect to FIG. 2, such as one of a sural nerve, peronealnerve, femoral nerve locations, or a nerve branch extending peripherallytherefrom.

In FIG. 2, the left-hand side illustrates the situation believed toexist in a symptomatic RLS patient. The RLS symptoms are believed to becaused by irritated or overactive Alpha-delta and C fibers that maycause ectopic neural activity that is interpreted as sensations ofdiscomfort, which can be modulated by a spinal cord 5-HT, opioid orcannabinoid receptor, which, in turn, can be affected by preferentiallyrecruiting (e.g., stimulating nerve fiber activity in) Alpha-beta fibersthat release inhibitory neurotransmitters (GABA) to suppress thisectopic activity pattern.

In FIG. 2, the right-hand side illustrates the situation believed toexist when an electrostimulation is appropriately tailored and deliveredto an appropriate target location (e.g., to one or more of a sural,peroneal, or femoral nerve to one or more peripherally extendingbranches thereof). The tailored electrostimulation at one or more ofthese particularly selected target nerve locations (e.g., one or more ofa sural, peroneal, or femoral nerve to one or more peripherallyextending branches thereof) can active faster-conducting Alpha-betafibers, which, in turn, can stimulate production of GABA by the spinalcord 5-HT, opioid or cannabinoid receptor, which, in turn can calm theslower-conducting Alpha-Delta or C fibers inhibiting overactivity orirritating impulses from being generated and conducted by theAlpha-Delta or C fibers.

One technique for assessing efficacy of treatment of RLS symptoms is toperform a suggested immobilization test (SIT). In the present case, theSIT test can be performed before administering therapy, and thencontinued or performed again during or after administering therapy. Aspart of the SIT, patients can be asked to sit upright on a bed with legsstretched outward, such as for a duration of 60 minutes, with legmovements recorded (e.g., using an accelerometer or other leg-movementsensor) and asked to score their discomfort, such as on a scale of 0 to10, every 10 minutes for the entire 60-minute duration.

FIG. 3 shows an example of experimental SIT data from a patient withsevere RLS, who was on medications (which medications were not withheldfor the SIT study). The “baseline” SIT data (without any appliedelectrostimulation) shown in FIG. 3 shows increasing discomfort duringthe initial 20 minutes of the SIT study, followed by a steady level ofdiscomfort at about 60% of the maximum discomfort level for theremainder of the SIT study. The “therapy” SIT data (with appliedstimulation after the initial 20 minutes) was obtained from the samepatient on the following night. The electrostimulation wastranscutaneously applied to both the superficial peroneal nerves using ahydrogel-coated transcutaneous electrode, connected to aconstant-current stimulator programmed to generate a waveform thatstimulated the nerve with pulses that were 80-100 microseconds induration, with an interval of 240-250 microseconds between them. Theelectrostimulation was turned on at minute 20. The patient reported anearly instant relief from uncomfortable sensations in the feet when theelectrostimulation therapy was turned on. The electrostimulationwaveforms and amplitudes chosen were subsensory (such that theelectrostimulation could not be sufficiently felt by the patient) andsubthreshold (such that muscle activation did not occur in the patientas evidenced by any visual twitching or other sensations reported bypatient), such that the patient could not identify whether therapy wasturned on or off. Subsensory and subthreshold electrostimulation can beparticularly beneficial in the present RLS application, such as toalleviate RLS symptoms while avoiding or minimizing the patient'sperception of the electrostimulation being administered, such as toallow the patient to be able to fall asleep comfortably.

FIG. 4 shows an example summarizing SIT data results “before” and“after” electrostimulation of the superficial peroneal nerve target ofsix RLS patients that all met the criteria for “severe” RLS based on theInternational Restless Legs Syndrome Score (IRLSS) administered prior toenrollment. FIG. 4 demonstrates an example of a remarkable consistencyin decrease of uncomfortable sensations associated with RLS in responseto turning on electrostimulation of the superficial peroneal nerve.

Electrostimulation waveforms can be chosen specifically in frequency,shape, and amplitude such as to activate the large diameter A-Betafibers that act to “gate” or block inputs from the smaller diameterA-Delta and C fibers that, in RLS patients, appear to be overactive andto transmit unpleasant sensations to the spinal cord, such as explainedherein with respect to FIG. 2. In an example, a controlled-currentelectrostimulation waveform can be used, such as a charge-balancedsquare wave current waveform with current amplitudes delivered at acontrolled current level that is between 5 milliamperes and 30milliamperes or, such as was used for the patients represented in FIG.4, at a controlled current level that is between 11 milliamperes and 25milliamperes.

The present inventor has recognized, among other things, that highfrequency (“HF”, e.g., at a frequency between 500 Hz and 15,000 Hz, oreven more particularly, between 4 kHz and 5 kHz) transcutaneouselectrostimulation current waveforms can be—in this RLSapplication—preferred over low frequency (“LF”, e.g., 150 Hz or below)transcutaneous electrical neurostimulation (TENS) waveforms. This isbecause, in an RLS therapy application, it is important to target theseperipheral nerve fibers (such as the superficial peroneal nerve) with asubthreshold electrostimulation waveform that does not induce musclecontractions, as well as with a subsensory electrostimulation waveformthat does not induce sharp sensations of electrostimulation (like mostconventional LF sensory TENS waveforms, e.g., at 150 Hz or below), asthis was observed to make RLS symptoms worse. Without being bound bytheory, this could be attributed to patients with RLS having a stronghyper-sensitivity to any physical touch (tactile hyperalgesia) when RLSsymptoms present and has been studied in the literature. Switching to ahigh-frequency (e.g., 4000 Hz-5000 Hz) subsensory electrostimulationwaveform showed a marked improvement in RLS symptoms in some patients,such as shown in the example SIT data of FIG. 5.

FIG. 5 shows an example of SIT data from a patient study in which a LFconventional (150 Hz) “Burst”-TENS electrostimulation waveform wasturned on at minute 20, then switching directly to a HF (4000 Hz-5000Hz) electrostimulation waveform at minute 30. During the initial 20minutes of this SIT study (without any electrostimulation) patientdiscomfort climbed from 0 to 80% of the maximum possible score. With LFTENS electrostimulation, the patient's discomfort level actuallyincreased to 90% of the maximum possible score. But after then turningon HF electrostimulation, the patient's discomfort level fell to 50% ofthe maximum possible score, indicating marked relief as compared to noelectrostimulation or as compared to LF TENS electrostimulation.

Without being bound by theory, it is believed that this acutesuppression of RLS symptoms using HF electrostimulation is because ofthe selective recruitment (e.g., activation via electrostimulation) ofA-Beta fibers in the nerve targeted, which, in turn triggers release ofGABA to block out the overactive A-Delta and C fibers, such as explainedabove with respect to FIG. 2. A sensed waveform indicating suchselective activation may be obtained. This can include recording anevoked response from the electrostimulation stimulus (such as using aneural recording sense amplifier channel such as described herein), and,if needed, by re-adjusting one or more parameters of theelectrostimulation stimulus, such as to obtain a desired pattern ofactivation, such as indicating selective recruitment of A-Beta fibers inthe nerve targeted.

FIG. 6 illustrates conceptually an example of a resulting compoundaction potential (CAP), and the contribution of each nerve fibersub-type, that can be sensed and recorded along the length of the samenerve to which an electrostimulation is applied at a distance “L” awayfrom the location of the applied electrostimulation. Sensing at twodifferent distances “L” from the electrostimulation location are shownin the conceptual example of FIG. 6. At a larger distance of separation“L” conduction latency differences between the different nerve fibersub-types can contribute to a unique morphology indicating whichsub-type of nerve fiber has been selectively or preferentially recruitedby a particular electrostimulation, such as relative to one or moreother nerve fiber sub-types.

For example, in FIG. 6, at a smaller distance of “L” (e.g., ˜1 inch or25 mm), it can be difficult to observe each nerve-fiber component thatcontributes to the average CAP with the respective conduction velocitiestaken into account. However, if the sensing/recording electrode is movedfarther downstream from the electrostimulation electrode along thelength of the nerve, such as at a length “L” of ˜80 mm or greater, theseparate nerve-fiber components start to show up on the CAP asindividual peaks. This is shown conceptually in FIG. 6 over a timeperiod of about 60 ms after electrostimulation.

Based on a sensed/recorded CAP, it is possible to configure or optimizeone or more electrical stimulation waveforms, such as to preferentiallyactivate only a select sub-set of fibers, such as the A-Beta fibers.This method of detecting nerve fiber activation has been studied andreported in the technical literature. (See, e.g., Qing et al, IEEE TransNeural Syst Rehabil Eng. 2015 November; 23(6):936-45.)

FIG. 7 illustrates a conceptual example of how each individual nervefiber component may be detected. This can include using a neuralrecording amplifier system that can be connected to a recordingelectrode that can be placed at one or more specified locations alongthe length of the nerve being stimulated upstream thereto.

FIG. 8 illustrates a conceptual example of three different recordingelectrode waveforms. In the example of FIG. 8, the top waveform shows anexample of an evoked response case in which no particular nerve fibertype is selectively or preferentially recruited by an appliedelectrostimulation. In FIG. 8, the middle waveform shows an example ofan evoked response waveform in which the C fiber has been preferentiallyrecruited by an applied electrostimulation, as indicated by the presenceor dominance of a slower, lower frequency C fiber evoked potential overthe absence or omission of a faster higher-frequency A-Delta evokedpotential. The bottom waveform shows an example of an evoked responsewaveform in which the A-Delta fiber has been preferentially recruited byan applied electrostimulation, as indicated by the presence of dominanceof a faster higher-frequency A-Delta evoked potential over the absenceor omission of a slower, lower frequency C fiber evoked potential.

In an example, a CAP can be sensed, recorded, or measured. One or moreparameters of the electrostimulation can be adjusted or optimized, suchas to obtain a desired CAP response, such as one indicating preferentialrecruitment of one or more specific nerve fiber sub-types, such aselective recruitment of A-Delta fibers, such as explained herein. Thesystem can include or use a set of transcutaneous electrodes toelectrostimulate a designated target location of a target nerve, such asa targeted peripheral nerve (e.g., peroneal, sural, femoral, or a branchthereof, as an example) and a recording electrode can be locateddownstream of the targeted nerve or its targeted branch, such as torecord a resulting evoked response signal.

In an illustrative, non-limiting example, first, a burst of electricalstimulation can be applied at the specified electrostimulation location,such as at a specified frequency (e.g., a frequency between 4 and 5kiloHertz) such as for a specified duration (e.g., <10 milliseconds).Second, using hydrogel recording electrodes located at a specifieddistance from the electrostimulation electrode location, a resultingevoked CAP can be sensed using an electrically connected neuralamplifier channel. Third, the electrostimulation intensity can beincreased, such as until maximal evoked CAP amplitude is observed in thesensed or recorded signal. Fourth, one or more components A-Delta,A-Beta, or C fiber contributions from their characteristic individualpeaks can be detected and averaged, such as over multiple bursts ofelectrostimulation. Fifth, one or more electrostimulation parameters canbe adjusted, such as to modify the recorded CAP component amplitudepeaks, such as to preferentially recruit one nerve fiber type subsetover another, for a lower intensity of electrostimulation stimulus.

Similarly, to detect whether a particular electrostimulation waveform ispreferentially recruiting one or more nerve fiber type subsets overanother, the electrostimulation device under test (DUT) can be appliedto a test impedance representative of a nerve target, such as tocharacterize the electrostimulation waveform. Then, the characterizedelectrostimulation waveform can be applied to a target nerve location,such as to observe the downstream evoked CAP and components attributableto one or more nerve-fiber types. Then, one or more parameters of theelectrostimulation waveform can be varied, such as to determine whethera particularly emphasized component evoked in response to thepreviously-characterized electrostimulation waveform diminishes ordisappears, such as relative to one or more other components of theevoked response waveform. For example, if one or more parameters of theelectrostimulation parameters results in diminishing the A-Deltacomponent observed in the evoked CAP relative to the C component of theevoked CAP, then it can be concluded that the characterizedelectrostimulation waveform was specifically tailored to preferentiallyrecruit an A-Delta nerve fiber sub-type relative to a C fiber sub-type.Without being bound by theory, as explained herein, this can bedesirable, such as to release GABA in the dorsal horn of the spinalcord, such as to help inhibit or suppress ectopic discharge activityfrom the targeted nerve, such as to alleviate one or more RLS symptoms.

Without being bound by theory, as explained herein such as with respectto FIG. 2, the activation of the larger diameter A-Beta fibers (or TypeII fibers according to Lloyd's classification) has an inhibitory effect,such as by promoting the release of GABA that inhibits activity from thenoxious stimuli carrying fibers (A-Delta and C fibers or Type III andType IV, respectively). This was explained with respect to FIG. 2, andhas been validated by the present inventor with clinical resultsobtained from patients with severe RLS symptoms.

In an example, the signaling cascade such as described with respect toFIG. 2 can be accomplished such as by activating one or more selectedfibers (e.g., such as the A-Beta), such as in one or more peripheralnerves, such as a superficial peroneal or sural nerve (or branchthereof), which has demonstrated a near-instantaneous suppression of RLSsymptoms. In an example, this can be established such as by using anelectrostimulation with a carefully selected waveform, such as can rangein frequency from 500 Hz to 10,000 Hz, in pulse width from 50 μS to 1ms, and in current amplitude from 1 to 30 mA.

In a particular example, clinical data was obtained by switching betweena LF waveform at 150 Hz and another, HF, waveform at 4,000 Hz with apulse width of 50-100 μs. This allowed comparison of efficacy between LFand HF waveforms.

In another example, a 4000-5000 Hz randomly varying frequency waveformcan be applied at the same time as a second waveform, which can beseparated in frequency from the first, such as by 100-150 Hz, and canalso be vary in approximately the same 4,000-5,000 Hz range (e.g.,second frequency varying between 4100-5100 Hz).

FIG. 9A shows an example of SIT data in which HF electrostimulation wasturned on after an initial period of 20 minutes, providing nearinstantaneous suppression of RLS symptoms, and then turned off again at40 minutes, triggering a resumption of RLS symptoms, furtherdemonstrating acute efficacy of the HF electrostimulation, which isbelieved to provide the benefit of our proposed mechanism of action suchas described above with respect to FIG. 2.

FIG. 9B shows an example of electrostimulation sensory comparative datafor typical low frequency (LF) transcutaneous electricalneurostimulation waveforms as compared to a (HF) transcutaneouselectrostimulation waveform according to the present techniques in N=5normal subjects.

The parameters of the HF electrostimulation waveform can be carefullyselected, such as to ensure maximal target nerve fiber activation forthe least possible sensory perception threshold reported by patients. Asshown in FIG. 9B, in randomized, blinded experimental tests performed onN=5 healthy controls, the HF electrostimulation waveform was applied ata frequency that was selected to be between 4000 and 5000 Hz—which wasconsistently able to deliver higher amounts of electrical current to thetissue before any sensory perception was reported by the patient, ascompared to a typical LF TENS waveform at 150 Hz or below. Similardifferences are also seen in thresholds at which patients reporteddiscomfort, as shown in FIG. 9B.

FIG. 9C shows, according to calculations based on waveform shape andpulse widths, the HF waveforms (e.g., between 4000 and 5000 Hz) of thepresent techniques are able to inject 47 to 49 times more charge intothe target tissue than conventional LF TENS (e.g., at 150 Hz or below)before the electrostimulation becomes perceptible, or before theelectrostimulation becomes uncomfortable.

FIGS. 9D and 9E illustrate an example of using a Flexion Reflex response(Fr) to electrostimulation technique (e.g., that can be usedadditionally or alternatively to the CAP technique described herein)such as to establish or refine an electrostimulation waveform pattern,in patients receiving therapy. The flexion or flexor reflex (Fr) is aneurophysiological tool such as can be used to assess the efficacy ofanalgesic therapies, as stated by the European Federation ofNeurological Societies (EFSN) guidelines. This Fr response can beelicited by electrical stimulation of a sensory nerve (e.g., suralnerve) and can be recorded from the flexor muscle in the ipsilaterallimb (e.g., biceps femoris). The Fr includes an early response, the RIIreflex (RIIr), and a late response, the RIII reflex (RIIIr). The RIIr isa non-nociceptive A-beta fiber mediated response, whereas the RIIIr is ahigh-threshold nociceptive A-delta fiber mediated reflex; the thresholdof the RIIIr has been shown to correspond to the pain threshold and thesize of the reflex to be related to the level of pain perception. TheRIIIr is the more stable and reliably measured reflex and its amplitudeis correlated to the intensity of pain perception, correlated to amountof nociceptive A-Delta activation.

In an example, the lower-limb flexion response may be elicited bydelivering percutaneous electrical stimuli to the sural nerve throughsurface electrodes applied behind the right lateral malleolus andrecording responses from the ipsilateral brevis head of the bicepsfemoris muscle. The stimulus can include a train of 5 electrical pulses(e.g., 1 to 5 milliseconds in duration, at a frequency that is between100 and 250 Hz) and can be delivered randomly or pseudo-randomly such asat an interval that is between 5 and 20 seconds. FIG. 9D shows aconceptualized (not real data) example of such a Flexion Reflex (Fr)response to a test electrostimulation stimulus. The amount of stimuluscurrent required to produce a reliable RIIIr waveform can be logged asthe sensory threshold, and the electrostimulation can then be adjustedto be sub-sensory, such that it is beneath the sensory threshold of thepatient and is not felt by the patient.

When the HF electrostimulation waveform is applied at a peripheral nerve(e.g., superficial peroneal nerve), a decrease in the amplitude of theflexion reflex response (RIIIr component) may be observed, indicating aresult of the inhibitory cascade of neural activation described in FIG.2, with a conceptual (not real data) example illustrating how this canbe measured shown in FIG. 9E.

In FIG. 10, the RLS treatment system 1000 can include a controllercircuit 1002, a battery 1010, a power converter circuit 1008, anelectrostimulation waveform generator circuit 1006, a user input device102, and patient electrodes 1014. In an example, the patient electrodescan include external electrodes, such as can be located on an adhesiveskin-patch, such as for transcutaneous application of electrostimulationenergy. In an example, the patient electrodes can include an implantableelectrode, such as a nerve cuff that can be implanted such as toencircle a targeted nerve (e.g., a sural nerve) at a targeted locationto position electrodes at the desired location. Implantable electronicscan be included on the nerve cuff, such as to control delivery of theelectrostimulation. The implantable electronics can be powered all or inpart by RF or inductively-coupled energy that can be wirelessly coupledfrom an external transcutaneous electrical transmission (TET) source toan energy-receiving device on the implantable electronics.

The controller circuit 1002 can include a microprocessor,microcontroller, programmable logic circuit, or the like, such as can bepowered by the battery 1010 or other power source. The battery can becoupled to a power converter circuit 1008, such as can include one ormore of a buck power converter circuit, a boost power converter circuit,a buck-boost power converter circuit, or other inductive or capacitiveor other circuit for converting the battery voltage and current to adesired output voltage and current such as for deliveringelectrostimulation to the subject via the patient electrodes 1014. Anelectrostimulation waveform generator circuit 1006 can receive aconverted power signal from the power converter circuit 1008, and cangenerate a suitable electrostimulation waveform, such as a HFelectrostimulation waveform such as described herein. For example, theelectrostimulation waveform generator can be configured by thecontroller circuit 1002 to generate a HF electrostimulationcontrolled-current waveform such as having a frequency within a range of4 kHz to 5 KHz and a current amplitude that can be controlled by thecontroller circuit 1002 such as set to a desired level such as within arange of 5 milliamperes to 30 milliamperes (e.g., at a level of 5 mA, 10mA, 15 mA, 20 mA, 25 mA, or 30 mA, or finer resolution if desired).

In the example of FIG. 10 and the open-loop RLS treatment system 1000, atimer circuit 1004 can be included in or coupled to the controllercircuit 1002, such as to control a duration for which the RLSelectrostimulation treatment is applied after being turned on, such asby using a switch or other user input 1012 device. After the “on”duration established by the timer expires, the RLS electrostimulationtreatment can be automatically turned off, thereby saving powerextracted from the battery 1010. In an example, the timer duration canbe an expected duration for the patient to fall asleep with the aid andassistance of the RLS electrostimulation treatment, such as at aprogrammable or other specified treatment duration value (e.g., 10minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50minutes, 55 minutes, 1 hour, or the like). In an example, the therapycan be ramped down upon expiration of the timer, rather than beingabruptly turned off. The rampdown period can be specified, such as at aspecified percentage of the treatment duration (e.g., 10%, 20%, 30%,40%, 50%, or the like). The timer circuit 1004 can include a clockcircuit, such that a time-of-day can be used to trigger aelectrostimulation treatment session, such as of an electrostimulationtreatment duration value as can be timed by the timer circuit 1004, suchas described above.

FIG. 11A shows an example of a closed-loop RLS electrostimulationtreatment system 1100, which is similar to the open-loop RLSelectrostimulation treatment system shown in and described with respectto FIG. 10, but in which the timer 1004 can be replaced or augmented bya sensor circuit 1104. The sensor circuit 1104 can be used to sense aphysiological or other similar parameter of the patient, and to controltherapy using information about the parameter sensed by the sensorcircuit 1104.

For example, such as where the RLS electrostimulation treatment system1100 is worn on the patient's foot or lower limb, the sensor circuit1104 can include an accelerometer or other motion sensor, such as can beconfigured to sense a leg motion of the patient. Information about thesensed leg motion can be used by the controller circuit 1002 to controla parameter of the electrostimulation. For example, electrostimulationcan be turned on when a threshold number of symptomatic RLS leg twitchesor motions have been sensed within a specified first sensing duration(e.g., within a duration that can be specified at 1 minute, 2 minutes, 5minutes, or the like). This can be useful, for example, in a PLMDpatient who can experience leg twitches or motions while sleeping, suchas to automatically turn on (or increase) therapy to help mitigatesymptoms to help the patient stay asleep. In an example,electrostimulation can be turned off (or can be ramped down or rampedoff) when no RLS leg twitches or motions have been sensed within asecond sensing duration (e.g., within a duration that can be specifiedat 1 minute, 2 minutes, 5 minutes, or the like). In an example, anelectrostimulation amplitude can be increased when RLS twitches ormotions have been sensed within a specified third sensing durationduring which RLS electrostimulation therapy was being provided (e.g.,persist beyond a duration that can be specified at 5 minutes, 10minutes, or the like).

In an example, the sensor circuit 1104 can include a heart ratevariability (HRV)-based or other sleep sensor, such as can be configuredto sense whether the patient has fallen asleep, after whichelectrostimulation can be turned off (or can be ramped down or rampedoff), or to detect a sleep state, and adjust an electrostimulationparameter based on the sleep state of the patient. The sleep sensor canbe included and used together with the accelerometer, such as to detectleg twitches or motions while the subject is asleep, and automaticallyturn on (or increase) electrostimulation therapy in response. This canbe useful for a PLMD patient who can experience leg twitches or motionswhile sleeping, such as to automatically turn on (or increase) therapyto help mitigate symptoms to help the patient stay asleep.

FIG. 11B shows an example of a block diagram of portions of an RLSelectrostimulation system 1110, such as can be configured to produce acontrolled-current waveform (e.g., specified constant current amplitudeAC electrostimulations) across a varying impedance present at aninterface between the electrostimulation electrodes 1014 and the skin orother tissue of the patient contacted by such electrostimulationelectrodes 1014.

In FIG. 11B, a power management circuit 1118 can be electricallyconnected or otherwise (e.g., wirelessly) interfaced to a power source,such as one or more rechargeable or other batteries 1110. The powermanagement circuit 1118 can monitor a battery usability indication, suchas can provide information about the amount of charge or other indicatorof usable life remaining in the battery 1110. The power managementcircuit 1118 can provide an alert or can trigger automatic recharging(e.g., wirelessly or otherwise) of one or more of the batteries 1110,such as when depleted below a programmable, specifiable, or otherthreshold value.

The battery 1110 can be electrically connected or otherwise interfaced(e.g., through the power management circuit 1118) to a buck-boost powerconverter circuit 1120, such as can generate a programmable output DCvoltage (e.g., 12V, 20V, 30V, or other specified DC output voltage. TheDC output voltage needed can be determined by the controller circuit1002, such as based on a sensed load impedance, which can vary, such asdue to a varying electrode-tissue interface impedance. The loadimpedance can be measured using impedance sensing circuitry 1119. Theimpedance sensing circuitry 1119 can include one or more current sensingresistors, such as can sense a current at the electrodes. The currentsensed by the current sensing resistors can be converted by the currentsensing resistors into a voltage signal. The resulting voltage signalcan be received at one or more inputs of an amplifier 1122, and can bebuffered or amplified by the voltage amplifier 1122. The resultingbuffered or amplified voltage signal can be digitized, such as by ananalog-to-digital converter (ADC) circuit, such as can be included in orcoupled to the controller circuit 1002.

The controller 1002 can use the sensed load impedance, which may be usedby the controller 1002 in combination with other information, such as todetermine the magnitude of the DC output voltage of the buck-boostconverter 1120 needed to generate the desired electrostimulations, suchas to conserve battery power while providing or maximizing therapeuticefficacy of the electrostimulations. The controller 1002 can establishone or more patterns of the desired electrostimulation, such as by usingone or more stored electrostimulation waveform parameters that can begenerated by the controller 1002. The controller 1002 can use the one ormore stored electrostimulation parameters, such as to generate one ormore analog electrostimulation control voltage waveforms, such as usinga digital-to-analog (D/A) converter 1106.

The resulting one or more generated analog electrostimulation controlvoltage waveforms can be converted to a proportionate, controlled,load-independent current, such as can include using one or moreoperational amplifier based current pumps 1108. The resultingcontrolled-current electrostimulation signals can be routed to a desiredcorresponding electrode 1014. Such routing can include using amultiplexer or switch matrix 1116. In an example, the switch matric 1116can include one or more single-pole double-thrown (SPDT) switches, suchas shown in the example of FIG. 11B, such as can be operated andcontrolled by the controller 1002, such as to dictate electrostimulationpolarity, direction of electrostimulation field generated, tocharge-balance or otherwise adjust or optimize the electrostimulationwaveform, such as by selectively interfacing the controlled-currentelectrostimulation signal with the tissue at one or more targetlocations, such as using the electrode contacts 1014. In an example, thecontroller 1002 can be interfaced with bidirectional or other wirelesscommunication circuitry 1017, such as can include a transceiver circuitthat can follow a protocol, such as Wi-Fi or Bluetooth, such as tocommunicate with or exchange information with a local external unit orwith a remote server. A user-input module 1012 can also be configured tointerface with the controller 1002, such as can include one or more aidsto interact with the patient, with a caregiver, or with another user,for example, such as one or more push buttons or LED lights, such as tocommunicate information, to provide one or more status updates, or toturn on or off the RLS electrostimulation system 1110 or one or morecomponents thereof.

One or more portions of the example shown in FIG. 11B can be combinedwith one or more portions of the example shown in FIG. 11A or with oneor more portions of the example shown in FIG. 10, or with one or moreportions of one or more other examples such as shown or describedherein.

FIG. 11C is a flow chart showing generally an example of portions of amethod 1130, such as can be performed using the RLS electrostimulationsystem 1130. At 1132, one or more electrostimulation parameters can beset up, such as by programming such information into memory storage inor coupled to the controller circuit 1002. Examples of suchelectrostimulation parameters can include one or more of amplitude,frequency, pulsewidth, duty cycle, pulse repetition frequency, or thelike. At 1134, a test electrostimulation waveform can be delivered tothe subject, such as via the electrodes 1014. At 1136, a load impedanceor a component thereof, such as electrode-skin interface impedance canbe calculated, such as by the controller circuit 1002, such as using asensed impedance signal that can be measured using the impedancemeasurement circuit 1119, which can be buffered or amplified by theamplifier circuit 1122. By issuing a known voltage amplitude signal andmeasuring a response current signal (or vice-versa), such impedance canbe determined. At 1138, the response signal data or calculated impedancedata can be logged, such as by storing it to a memory location, such aswithin the controller circuit 1002. At 1140, it can be determinedwhether the measured electrode-skin interface impedance is outside aspecified “normal” range, such as can include using one or morecomparator circuits within the controller circuit 1002 or elsewhere,which can be provided one or more reference values for comparison forestablishing the normal impedance range. If it is determined that themeasured impedance data is outside the normal range, then at 1142, analert can be generated to the patient or other user, such as to promptreplacement of the electrodes 1014, and an error condition can be loggedin the controller circuit 1117, or communicated to a local or remoteinterface device or server system. Otherwise, at 1140, if it isdetermined that the measured impedance data is within the normal range,then at 1144, the measured impedance data can be logged in thecontroller circuit 1117, or communicated to a local or remote interfacedevice or server system.

In FIG. 11C, after the skin-electrode interface impedance is calculatedat 1136, this information can be used at 1146 to establish the DC outputvoltage to be provided by the buck/boost converter circuit 1120, suchfor use in generating the appropriate HF electrostimulation waveform,such as described above with respect to FIG. 11B. At 1148, the generatedHF electrostimulation waveform can be applied to the patient via theelectrodes 1014. At 1150, the generated HF electrostimulation waveformcan be measured. This can include measuring the HF electrostimulationwaveform current, such as by measuring the voltage across a senseresistor to provide a measurement indicative of the electrostimulationwaveform current. At 1152, the measured value of the electrostimulationvalue can be compared to a saturation threshold value, such as caninclude using a comparator, such as can be included within thecontroller circuit 1102. If the result of the comparison indicates thepresence of a saturation condition, then at 1154, the DC output voltageof the buck-boost converter circuit 1120 can be increased for subsequentapplication of the electrostimulation energy. Otherwise, the DC outputvoltage of the buck-boost converter can be maintained for subsequentapplication of the electrostimulation energy.

FIG. 12 shows an example of a technique 1200 for using one or moresensor circuits 1104 or the user inputs device 102, or both, such as forcontrolling RLS electrostimulation therapy delivery, such as by theclosed loop RLS electrostimulation therapy system 1100. At 1202, forcontrolling RLS therapy delivery, one or more of user input can bereceived (1202A), 3D accelerometer input can be received (1202B), asensed heart rate (HR) or respiration input signal can be received(1202C), a sensed skin impedance input signal can be received (1202D),such as by the controller circuit 1002, such as for use in determiningwhether the patient is attempting to fall asleep at 1204, or whetheronset of sleep has been detected at 1206.

For example, a user can actuate a switch or can provide other user inputat 1202A, such as for signaling to the system 1100 that the patient isintending to fall asleep. Sleep detection can be performed by thecontroller circuit 1002, such as by using information from the 3Daccelerometer at 1202B to determine a position of the patient (e.g.,upright vs. recumbent) or of the patient's lower limb, or whether legactivity movement indicates RLS symptoms, such as leg twitches ormotion, or is consistent with sleep. A heart rate can be sensed (e.g.,via the patient electrodes 1014 or via separate electrodes that can beplaced or located in contact with the patient), and a heart ratevariability (HRV) parameter can be calculated by the controller circuit1002 from the sensed heart rate signal. HRV can be used to detect sleepor to detect a particular state of sleep. A respiration (breathing)signal can be sensed (e.g., via the patient electrodes 1014 or viaseparate electrodes that can be placed or located in contact with thepatient) such as by using an impedance sensor to detect respiration,which will modulate the detected impedance. Sleep state information canbe extracted from the respiration signal, such as by signal processingsuch as can be performed by the controller circuit 1002. Sleep stateinformation can also be obtained by interfacing with other sleepmonitoring products that a patient may use, such as can communicate thisinformation to the controller circuit 1002. A skin impedance sensor canbe used to detect frequency-dependent impedances using the patientelectrodes 1014 or other changes in skin impedance, such as can provideinformation about the subject's sleep state, such as by processing suchinformation as can be performed by the controller circuit 1002.

An autonomic balance sensor or indicator can be used to detect a stateof a balance between the subject's sympathetic and parasympatheticnervous systems. Such information can be used to adjust anelectrostimulation parameter. This can include adjusting anelectrostimulation level to provide a higher degree ofelectrostimulation corresponding to a higher level of sympatheticnervous system assertion relative to parasympathetic nervous systemassertion.

A posture sensor can be used to detect a state of a patient's posture,which information can be used to adjust one or more electrostimulationparameters. For example, in a patient with RLS symptoms that are worsewhen the patient is trying to sleep upright (e.g., in a seat on anairplane) as opposed to when the patient is trying to sleep while lyingdown in a recumbent position, such posture information can be used toincrease titration of electrostimulation therapy when the former caseoccurs, relative to when the latter case occurs.

At 1204, it can be determined whether the patient/user is attempting tofall asleep. For example, a user can actuate a switch or can provideother user input at 1202A, such as for signaling to the system 1100 thatthe patient is intending to fall asleep. In an example, a transition ofthe patient into a recumbent position can be used as an indication thatthe patient is attempting to fall asleep.

At 1204, if the patient/user is attempting to fall asleep, then at 1208,RLS electrostimulation therapy can be initiated or, if already ongoing,sustained. Otherwise, at 1204, if the patient/user is not attempting tofall asleep, then process flow can proceed to 1210, in which ongoing RLSelectrostimulation therapy (if any) can be ramped down and stopped. At1208, starting RLS therapy can include initiating therapy using aninitial set of electrostimulation parameter values, such as can include,in an example, a stored set of electrostimulation parameters, such ascan be selected based on previous efficacy in the patient. Such efficacycan be determined by user survey input ranking the efficacy, or bydetecting a quantity of RLS symptoms (e.g., leg twitches or movements)over time after initiating an RLS electrostimulation therapy session.Electrostimulation parameter values can also be chosen based on thestate of sleep (e.g., N1-N4, REM/NREM, or the like), such as can bedetected by the controller circuit 1002 either using one of the on-boardsensors 1104 or using a different sleep monitoring device that thepatient may use, such as can communicate with the controller circuit1002. As an example, the controller circuit 1002 can elect to chooseelectrostimulation parameter values that are optimized to have lowersensory perception when a light or early stage of sleep is detected suchas to prevent any disruption of sleep in the patient.

At 1206, if after initiating electrostimulation therapy sleep isdetected, then process flow can continue to 1210, such as to ceaseelectrostimulation or to ramp down therapy electrostimulation energytoward then ceasing electrostimulation. This can help save power andavoid unnecessary therapy while the subject is asleep. Otherwise, at1206, if after initiating electrostimulation therapy sleep is notdetected, then process flow can return to 1208, such as to sustainelectrostimulation therapy, such as until such time that sleep onset canbe detected at 1206.

FIG. 13 shows an example of a technique 1300, similar to the technique1200, shown in and described with respect to FIG. 12, but modified toaddress episodes of leg twitching or motion occurring after the subjectfalls asleep, such as can occur in PLMD patients. In the example of FIG.13, the technique 1300 can proceed as described with respect to FIG. 12until after sleep is detected at 1206.

At 1206, if sleep is detected, then monitoring can continue until aspecified period of time has elapsed (e.g., 10 minutes, 15 minutes, or20 minutes) with leg movement being absent, or being less than aspecified threshold amount of leg movement during and over the specifiedperiod of time, after which process flow can proceed to 1210, to ceaseor to ramp down and cease electrostimulation therapy. However, since ina PLMD patient, episodes of leg twitching or movement can recur whilethe subject is sleeping, process flow can proceed from 1210 back to1206, to continue to monitor the patient for sleep at 1206, and then forleg movement during sleep, at 1302. If such monitoring indicates thatthe patient has awoken, RLS electrostimulation therapy can be resumed at1208. If such monitoring indicates that the patient has continuedsleeping, but has experienced a sufficient degree of leg twitching ormovement during such sleep, then electrostimulation therapy can beresumed at 1208. Otherwise, any ongoing electrostimulation can be rampeddown and stopped at 1210, subject to further sleep monitoring at 1206and further leg movement monitoring at 1302.

FIG. 14 shows an example in which one or more of the open-loop RLSelectrostimulation systems 1000 or one or of the closed-loop RLSelectrostimulation systems 1100, or both, can be communicatively coupledto a remote server 1402 such as via a cloud or communication network1404. This can include optionally using a repeater or other localinterface device 1406, such as can establish a Bluetooth or otherlow-power wireless connection with a local RLS electrostimulation system1000, 1100, for interfacing with the remote server 1402.

Remote server 1402 can be used for logging, processing, or analysis ofdata from the individual RLS electrostimulation system 1000, 1100instances associated with respective patients. The remote server 1402can include a library of patient data, such as can include waveform andefficacy data from previous episodes of various patients. The remoteserver 1402 can include a neural network, artificial intelligence, ormachine learning system that can use efficacy data about waveforms usedin various patients obtaining various results, such as for recommendinga particular electrostimulation waveform or electrostimulation parameterto a particular patient, such as based on previous data from thatpatient or from a population of patients. Such recommendation can bebased at least in part on a similarity of one or more characteristicsbetween a target patient and patients in the patient population includedin the library.

FIG. 15 includes an example of a stabilizer, such as to carry or holdall or portions of an RLS electrostimulation system 1000, 1100 in place.In FIG. 15, the stabilizer can include a spandex or other elasticwearable and removable knee sleeve, such as can include an elasticpatella opening formed therein, such as to allow the patient's patellato protrude therefrom. A disposable or other detachable adhesive patchcan carry or hold integrated electronics of the RLS electrostimulationsystem 1000, 1100, and can also include integrated hydrogel or otherelectrodes, such as can contact the patient's skin through correspondingopenings in the knee sleeve such as can correspond to one or moredesired locations of the targeted nerve to which electrostimulation isto be delivered for RLS therapy. In this way, positioning relative tothe target nerve location can easily be made, such as by using thepatient's patella as a landmark with respect to which the sleeve ispositioned, which, in turn, can serve to appropriately position theelectrodes at the desired locations with respect to the correspondingtarget nerve locations.

FIG. 16A shows a multilayer example of various layers of the disposableor other detachable patch 1600, such as shown in FIG. 15 in use with theknee sleeve. In this example, the most proximal (closest to the patient)layer 1602 can include a peel-off layer over an adhesive underlayer withelectrode cutouts. The next most proximal layer 1604 can includehydrogel pockets or electrodes, such as can be similarly shaped andaligned with the cutouts in the layer 1602. The next most proximal layer1606 can include or carry an electronics unit of the RLSelectrostimulation system 1000, 1100, such as with conductive traces forproviding electrical contact with and connection to the electrodes inthe layer 1604 or to one or more other components. The next mostproximal layer 1608 can include a flexible battery and antenna, such aswith electrical connections to the underlying electronics unit that canbe carried by the underlying layer 1606. The next most proximal layer1610 can be the most distal layer, and can include an electricallyinsulating top layer, at least a periphery of which can be bonded to oneor more of the underlying layers. In an example, the electronics unitcan be detachable from the other components, such as using a clasp orlocking mechanism, such as to permit re-use of the electronics unittogether with disposability of the other components of the patch.

FIG. 16B shows an example of portions of a stabilizer, such as caninclude a multi-layer disposable or other user-attachable anduser-detachable patch 1620, such as can be separately attachable to adetachable (e.g., optionally re-usable) electronics unit 1640 (FIG.15C), and such as can optionally be used with the knee sleeve shown inFIG. 15. The patch 1620 is shown as sized, shaped, or otherwiseconfigured to be particularly suitable for placement to target aperoneal nerve or femoral nerve such as for delivering targetedelectrostimulation thereto. The detachable patch 1620 can include a toplayer 1622A, a middle layer 1622B, and a bottom layer, 1622C. Theselayers can be similarly shaped to each other, such that, when stacked,they can define circular, flared out, or other flared out ends or lobes.These ends can be interconnected by a rectangular or other strip of adesired length, such as to obtain a desired positioning of theelectrodes. The electrodes can be placed at appropriately spaced-apartdesired locations at the ends, or at an appropriate location on theinterconnecting strip, such as for delivering the electrostimulations toa targeted nerve location (e.g., femoral nerve, peroneal never, suralnerve, or one or more branches thereof, or the like). Including a returnelectrode 1624C at an appropriate location in a middle portion of theinterconnecting strip can provide a return electrode location that isclose to the electrodes at the ends, which can target desiredelectrostimulation nerve target locations, but safely away from othernerves (e.g., in a peroneal nerve target placement), such as can helpavoid undesired electrostimulation of such other nerves. In the bottomlayer 1622C, electrodes 1624 can include hydrogel pockets that can becarried at selected locations of the bottom layer 1622C, such as at oneor more desired locations at the ends of the bottom layer 162C2, or atone or more desired locations along the interconnecting strip of thebottom layer 1622C, such as for contacting underlying skin. The hydrogelcarried in such hydrogel pockets associated with the electrodes 1624 canbe electrically conductive. This can help provide low electrode-skininterface impedance for the electrodes 1624.

The middle layer 1622B can include vias 1626, 1627 and conductive traces1628, such as for interconnecting the electrodes 1624 to respectivemetal or other electrically conductive contacts 1630 on the top layer1622A, such as at one of its ends, or to one of the electrodes 1624 onthe bottom layer 1622C. A detachable electronics unit 1640 (FIG. 16C)can be attached to the top layer 1622A, such as with respective contactsmatching the locations of the contacts 1630. The contacts on thedetachable electronics unit 1640 (FIG. 16C) can be magnetized, such asto provide a magnetic attraction force with the contacts 1630 on the toplayer 1622A. This magnetic attraction force can hold the detachableelectronics unit 1640 (FIG. 16C) in place with respect to the top layer1622A, and can allow self-alignment of the detachable electronics unit1640 (FIG. 16C) to the appropriate contacts of the top layer 1622A.

FIG. 16C shows an example of placement of the detachable adhesive patch1620 of FIG. 16B, such as at a peroneal nerve target location, justbelow the knee on an anterior portion of the lower limb, with thedetachable electronics unit 1640 magnetically or otherwise attached tothe detachable adhesive patch 1620.

FIG. 16D shows an example of portions of a stabilizer, such as caninclude a multi-layer disposable or other detachable patch 1660, similarto the patch 1620 shown in FIG. 16B, but with the patch 1660 shownincluding 5 electrodes, as compared to the 3 electrodes of the patch1620 shown in FIG. 16B. In the example of FIG. 16D, the ends can includeflared circular or other lobes, such as can extend laterally in opposingdirections from each end of the patch 1660. The detachable electronicsunit 1640 can be attached over one of these lobes, in magneticself-alignment or otherwise, such as to provide aligned contact betweena similar arrangement of contacts on the detachable electronics unit1640 as the arrangement of contacts 1630 shown in FIG. 16C.

FIG. 16E shows an example of placement of the detachable adhesive patch1660 of FIG. 16D, such as at a peroneal nerve target location, justbelow the knee on an anterior portion of the lower limb, with thedetachable electronics unit 1640 magnetically or otherwise attached tothe detachable adhesive patch 1660.

FIG. 16F shows an example of a local external interface device 1670,such as can be used for wirelessly or otherwise charging or re-chargingone or more detachable electronics units 1640, such as by plugging intoan AC wall outlet power source, or for communicating data wirelessly toor from the one or more detachable electronics units 1640, such as viaBluetooth to a mobile phone application, such as for furthercommunication with a remote server.

FIG. 16G shows an example of a block diagram of the local externalinterface device 1670. The local external interface device can include acontroller circuit 1672, such as can interface with a power managementcircuit 1674, a battery charge management circuit 1676, a wirelesscommunications transceiver circuit 1678, and a memory interface circuit1680, such as can include or be coupled to an external memory driveinterface circuit 1682. The power management circuit can include anAC/DC converter circuit, and a buck converter, boost converter,buck-boost converter, or other DC-DC power converter circuit, such ascan generate an appropriate supply voltage for charging or re-chargingthe one or more electronics units 1640, such as via the battery chargemanagement circuit 1676.

As an alternative to the selective recruitment of certain nerve fibertypes using HF electrostimulation to stimulate GABA production, therebycalming RLS or PLMD leg twitching or motion symptoms, blockingconduction to the spinal cord of a target nerve (e.g., one or more ofthe peroneal, femoral, or sural nerves or one or more of their branches,or other nerve target) can be carried out to disrupt, inhibit, or calmRLS or other leg twitching or motion symptoms. For example, an ACwaveform can be applied directly to the nerve using a cuff electrodewrapped around it, such as for applying an HF electrostimulationwaveform thereto.

In an example of the present techniques, such a nerve conduction blockcan be achieved by transcutaneously modulating the desiredhigh-frequency blocking signal onto a lower frequency carrier signal,such as to effectively block conduction of electrical signals along thenerve without requiring an implanted electrode or device.

FIG. 17 illustrates an example of a transdermal chemical agent deliveryadhesive patch. In an example of the present techniques, conductionblocking can be obtained or assisted by applying a transdermal drug orchemical agent delivery adhesive patch with a topical anesthetic (e.g.,lidocaine, bupivacaine, capsaicin), such as can be triggered to contactand permeate the skin, such as upon activation by an electrical triggersignal such as can be generated by on-board electronics that can becarried by the transdermal drug delivery adhesive patch. In the exampleof FIG. 17, the patch can include a most proximal peel-off adhesivelayer, such as can include a topical anesthetic. A next more proximallayer can include an insulating layer, such as with cutouts to allowcontact to electrodes controlling the release of the chemical agent. Amore distal layer can include a detachable electronics module, such ascan be configured to control release of the chemical agent, such as toblock nerve conduction between the spinal cord and a target nervelocation (e.g., one or more of the peroneal, femoral, or sural nerves orone or more of their branches, or other nerve target), such as toalleviate one or more RLS symptoms such as leg muscle twitching ormotion.

FIG. 18 shows an alternative closed-loop ultrasound embodiment, such ascan provide ultrasound energy to one or more of the target nervelocations described herein (e.g., femoral nerve, peroneal nerve, orsural nerve). In this example, electrical energy can be converted toultrasound energy, such as using a piezoelectric transducer tuned to theultrasound frequency, and driven by an ultrasound-frequency electricalpulse generator circuit.

In an example, ultrasound energy can be delivered to the target nervelocations in the subject in combination with the HF RLSelectrostimulation described herein. In an example, nerve ablation(e.g., by RF heating or using a freezing agent) can be additionally oralternatively used to block nerve activity one or more of the targetnerve locations described herein (e.g., femoral nerve, peroneal nerve,or sural nerve).

FIGS. 19A-19B shows an example of a method of using the HF RLSelectrostimulation therapy described herein in conjunction withpharmaceutical therapy, such as to downwardly titrate the pharmaceuticaltherapy in stages as the HF RLS electrostimulation therapy is increased.In an example, this approach may be used to find an appropriatepharmaceutical treatment level that can avoid RLS augmentation or otherpharmaceutical side effects, or to wean the subject of pharmaceuticaltreatment entirely.

Patients suffering from RLS may complain about symptoms that are orbecome present in the evenings or at bedtime, thereby preventing thepatient from being able to fall asleep. Sleep onset latency can bedefined as the amount of time taken to accomplish a transition from fullwakefulness to sleep, such as to the lightest of non-REM sleep stage.Patients with RLS can have extremely long sleep latencies, which can beimproved using the therapies described herein.

As described herein, an actigraphic recording, a measure of sympathetictone (such as heart rate or, particularly, of heart rate variability), ameasure of sleep, such as an EEG, may be used to identify when thepatient is awake, waking, asleep, or falling asleep, and used to triggera therapy such as described herein to turn on and off appropriately, orto be adjusted to an appropriate level.

FIG. 20 shows an example of a technique that can be used to turn on andoff the HF RLS electrostimulation therapy such as described herein. Thepatient can turn on the therapy at bedtime, such as by actuating aswitch or other user interface device. Activity and sleep monitoring canbe triggered in addition to the therapy. If sleep onset is detected,then therapy can be stopped or paused, such as until waking is detected,at which time therapy can be resumed, with further monitoring ofactivity or sleep. If no sleep is detected, or if sufficient lower legmovement activity is detected, then therapy can be continued orincreased. A sleep quality report can be generated, such as usinginformation from the sleep detector, and which can include usinginformation about the therapy delivered.

Adaptation of Nerves and Mitigation

Neurostimulation therapy can decrease in effectiveness over an extendedperiod of time, especially when used continuously, such as can be thecase for devices with implanted electrostimulation electrodes. Such aneural accommodation or tolerance can be attributed to neuralreorganization (plasticity) or to attenuation of end organresponsiveness. Neural plasticity is the change of structure, function,and organization of neurons in response to a new experience. The presentRLS electrostimulation therapy system and techniques can include certainfeatures that can help make it less susceptible to such a decrease inefficacy over longer term chronic use.

First, the present RLS electrostimulation therapy system can beconfigured to be used only during periods of time when RLS symptomspresent (e.g., usually no more than a few hours on one or several nightsof the week). In an open-loop configuration, this can include using atimer, using a clock with time-of-day information, or both. In aclosed-loop configuration, this can include using one or more sensors,such as described herein, such as to detect when RLS or PLMD symptomsare present, or to detect a physiological indicator indicatingsusceptibility to or aggravation of RLS or PLMD symptoms (e.g.,over-assertion of sympathetic tone in a heart rate variability (HRV) orother indication of automatic balance), such as for controllinginitiation, titration, or adjustment of electrostimulation therapy basedon such sensor information, which can be used alone or in combinationwith the timer, the clock time-of-day information, or both. With the RLSelectrostimulation exposure time being limited, there is limited windowfor neural accommodation owing to plasticity.

Second, the present RLS electrostimulation therapy system can have itscontroller circuit 1002 configured to provide waveform variability oradaptations, such as to help counter possible neural accommodation. Thiscan include modulating one or more electrostimulation waveformparameters such as, for example, one or more of pulsewidth, amplitude,frequency, or burst-mode or inter-burst intervals.

FIG. 21 shows an example a possible RLS electrostimulation waveform,such as can be generated by the present RLS electrostimulation therapysystem. One or more of the electrostimulation parameters can be varied,e.g., over time from an initial setting. Examples of electrostimulationparameters that can be set or adjusted can include, for the square waveelectrostimulation waveform of FIG. 21, positive amplitude (A1),positive pulsewidth (PW1), negative amplitude (A2), negative pulsewidth(PW2), off time duration between successive electrostimulation pulses(tOFF).

FIGS. 22 and 23 show examples of waveform patterns that are specificallyconfigured to inhibit or prevent short-term neural accommodation. FIG.22 shows a gradual ramp up (e.g., with ramping duration RampON) or rampdown (e.g., with ramping duration RampOFF), or both, of one of more(amplitude A1, A2, or both, or pulse-width PW1, PW2, or both) parametersuntil the desired therapeutic dosage has been reached, while maintainingcharge-balanced electrostimulation, if desired. In addition to beinguseful to inhibit neural accommodation, ramp-up or ramp down can helpfurther reduce or avoid sensory perception of the RLS therapyelectrostimulation stimulus. The therapy stimuli waveforms may also beseparated by an “off” period (BurstOFF) between bursts, such as shown inFIG. 22. This can help further reduce the exposure of any repeatingpattern to the target nerve while still maintaining therapeuticefficacy.

FIG. 23 shows a technique by which the primary electrostimulationwaveforms may be separated by “off” periods (BurstOFF), during whichsmaller secondary bursts of electrostimulation therapy can be applied,for example, as micro-bursts. The smaller secondary bursts of therapycan inject lesser charge into the nerve, such as by using a decreasedamplitude, decreased pulse-width, or altered frequency.

Additionally or alternatively, the RLS electrostimulation therapywaveform may also be varied, such as in a fixed frequency range around acenter frequency (e.g., 4000 Hz) in each burst, such as to furtherreduce any perceived or detected accommodation-related decrease intherapeutic efficacy. These actions may be triggered by user input ofRLS discomfort scores, or automatically, such as by the RLSelectrostimulation system controller circuit reviewing collected sensordata indicating RLS or PLMD symptoms or related physiological factors,such as leg-movements, hours of use per night, amplitude settings, andreported IRLSS score improvements. The RLS electrostimulation waveformparameters may also be modified, such as to help ensure that there is acontinued decrease in measured flexion response from the patient, suchas to maintain subsensory RLS electrostimulation. For example, if theamplitude of the flexion response (Fr-III) increases over time with useof RLS electrostimulation therapy, one or more of the RLSelectrostimulation therapy parameters may again be re-programmed, suchas to help promote or ensure continued minimization of this flexionresponse, such as shown in FIG. 24. Additionally, or alternatively, aninterferential current therapy approach can be used within the HFfrequency range, such as to help inhibit, suppress, or prevent neuralaccommodation.

Various Notes and Aspects

Although the present description has referred to RLS and RLS therapy,including HF RLF electrostimulation therapy, the present techniques fordetecting or treating RLS can also be applicable to PLMD, during whichsimilar symptoms (leg twitching or motions) can occur during sleep.

A numbered non-limiting list of aspects of the present subject matter ispresented below.

Aspect 1 can include or use subject matter (such as an apparatus, asystem, a device, a method, a means for performing acts, or a devicereadable medium including instructions that, when performed by thedevice, can cause the device to perform acts), such as can includeproviding treatment of one or more symptoms associated with RestlessLegs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD), such ascan include using applied high-frequency electrostimulation. This caninclude locating at least one electrostimulation electrode at a locationassociated with at least one of, or at least one branch of, a suralnerve, a peroneal nerve, or a femoral nerve of a subject with RLS orPLMD. Electrostimulation can then be delivered to the location to helpreduce or alleviate the one or more symptoms associated with RLS orPLMD.

Aspect 2 can include or use, or can optionally be combined with thesubject matter of Aspect 1 to include or use delivering subsensory(e.g., not felt), subthreshold (e.g., muscles not activated), AC highfrequency (HF) electrostimulation to the location, such as at a HFfrequency that exceeds 500 Hz and is less than 15,000 Hz to help reduceor alleviate the one or more symptoms associated with RLS or PLMD.

Aspect 3 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-2 such that the deliveringelectrostimulation includes delivering controlled-currentelectrostimulation.

Aspect 4 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-3 such that deliveringcontrolled-current electrostimulation includes delivering at acontrolled current level that is between 5 milliamperes and 30milliamperes.

Aspect 5 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-4 such that deliveringelectrostimulation includes delivering charge-balanced ACelectrostimulation. For example, this can include positive-goingwaveform portions delivering an amount of charge that is balanced out bynegative-going waveform portions.

Aspect 6 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-5, such as can includedelivering electrostimulation is at a frequency that is between 4 kHzand 5 kHz.

Aspect 7 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-6, such as can includedelivering subsensory and subthreshold electrostimulation such as can beestablished at or adjusted to a level that is not felt by the subjectand does not induce muscular contraction in the subject.

Aspect 8 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-7, such that the deliveringelectrostimulation includes using a waveform to activate A-Beta fibers,e.g., preferentially over other nerve fiber types at the target nervelocation.

Aspect 9 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-8, such as can includedelivering electrostimulation using a waveform that can be selected suchas to activate A-Beta fibers (e.g., preferentially) such as to releaseGABA to help inhibit overactive A-Delta fibers, C fibers, or both.

Aspect 10 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-9, such as can includedelivering controlled-current electrostimulation such as using an energylevel that or other electrostimulation characteristic value that can beestablished or adjusted based on a measured electrode-skin interfaceimpedance.

Aspect 11 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-10, such as can include usingan electrostimulation waveform that can elicit a resulting measuredcompound action potential (CAP) having a higher amplitude ratio ofA-Beta fiber to C fiber components recorded at a (e.g., peripherallyextending) distance from the electrostimulation electrode along atargeted nerve or branch thereof, such as an associated one of a suralnerve, a peroneal nerve, or a femoral nerve, as compared to an amplituderatio from a recorded response to a reference electrostimulationwaveform having a frequency of 150 Hz.

Aspect 12 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-11, such as can includedelivering electrostimulation that can be established or adjusted, suchas based on a measured load impedance or component (e.g., anelectrode-skin interface impedance) thereof.

Aspect 13 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-12, such as can includeselecting or receiving a subject presenting with RLS or PLMD. Further,this can optionally include selecting the subject as not presenting withat least one of peripheral neuropathy or RLS augmentation, e.g., beyondthe subject's legs.

Aspect 14 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-13, such as can be triggeredor adjusted automatically, such as in response to a sensor or otherindication of an RLS symptom of the subject.

Aspect 15 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-14, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to a sensor or other indication of anPLMD symptom of the subject.

Aspect 16 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-15, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to time-of-day information (e.g.,from a clock or timer circuit).

Aspect 17 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-16, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to a sensor or other indication ofposture of the subject.

Aspect 18 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-17, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to a sensor or other indication ofsleep status or sleep state of the subject.

Aspect 19 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-18, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to a sensor or other indication of anautonomic balance of the subject (e.g., heart rate variability (HRV) orthe like).

Aspect 20 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-19, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to a sensor or other indication ofone or more of leg or foot movement of the subject (e.g., from anaccelerometer).

Aspect 21 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-20, such as can includedelivering electrostimulation that can be triggered or adjusted, such asautomatically, such as in response to an indication of a drug therapy ofthe subject. For example, an RLS electrostimulation therapy treatmentplan can gradually increase electrostimulation energy levels over aperiod of time that can be long enough to gradually decrease an RLS drugtherapy to the subject.

Aspect 22 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-21, such as can include usinginformation about the delivered electrostimulation (or a physiologicalresponse to the delivered electrostimulation) to influence a drugtherapy of the subject. For example, this can include deliveringelectrostimulation and measuring a flexion response or a compound actionpotential (CAP) response, and using such physiological responseinformation to determine whether or how to titrate one or more drugsdelivered to the patient.

Aspect 23 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-22, such as can includecommunicating information about the delivered electrostimulation, itsefficacy (e.g., such as a measured physiological parameter measured inassociation with providing therapy), or the one or more symptoms (e.g.,leg movement, sleep status, or the like) to a local or remote externaldevice (such as a local interface device or a remote server device).

Aspect 24 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-23, such as can includelocating an electrostimulation electrode at an external locationassociated with a sural nerve or at least one branch (e.g., directlyconnected peripherally extending) branch thereof.

Aspect 25 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-24, such as can includelocating an external electrostimulation electrode at a locationassociated with a peroneal nerve or at least one branch (e.g., directlyconnected peripherally extending) thereof.

Aspect 26 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-25, such as can includelocating an electrostimulation electrode at an external locationassociated with a femoral nerve or at least one branch (e.g., directlyconnected peripherally extending) thereof.

Aspect 27 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-26, such as can includelocating an electrostimulation electrode at an external location at ornear a knee of the subject.

Aspect 28 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-27, such as can includelocating the electrostimulation electrode such as can include placing aknee sleeve about the subject's leg at the subject's knee.

Aspect 29 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-28, such as can includelocating the electrostimulation electrode at an external location at ornear a heel of the subject.

Aspect 30 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-29, such as can includelocating the electrostimulation electrode at an external location at ornear a peroneal nerve target below a patella and just below a tibialtuberosity on an anterior portion of the subject's lower limb.

Aspect 31 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-30, such as can includedelivering electrostimulation triggered in response to at least one of:an RLS or PLMD symptom, a time-of-day, a posture indication, asleep-status indication, an autonomic balance indication, or a leg orfoot movement indication.

Aspect 32 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-31, such as can includetranscutaneously delivering the electrostimulation via an externalelectrode located on the subject.

Aspect 33 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-32, such as can includetreating one or more symptoms associated with Restless Legs Syndrome(RLS) or Periodic Limb Movement Disorder (PLMD) using appliedelectrostimulation. This can include locating at least oneelectrostimulation electrode at a location associated with at least oneof, or at least one branch of, a sural nerve, a peroneal nerve, or afemoral nerve. It can include delivering, subsensory, subthreshold, ACelectrostimulation using a waveform configured to provide a resultingmeasured compound action potential (CAP) having an increased amplituderatio of A-Beta fiber to C fiber components recorded at a distance fromthe electrostimulation electrode along an associated one of a suralnerve, a peroneal nerve, or a femoral nerve relative to a referenceelectrostimulation waveform at 150 Hz.

Aspect 34 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-33, such as can includetreating one or more symptoms associated with Restless Legs Syndrome(RLS) or Periodic Limb Movement Disorder (PLMD) using appliedhigh-frequency electrostimulation. An electrostimulation electrode canbe located at a location associated with at least one of, or at leastone branch of, a sural nerve, a peroneal nerve, or a femoral nerve. Asubsensory, subthreshold, AC electrostimulation can be delivered, suchas using a waveform configured to release GABA, such as to provide aresulting higher measured increase in GABA relative to any increase inGABA elicited from a 150 Hz reference electrostimulation waveform.

Aspect 35 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-34, such as can include oruse a device for treating one or more symptoms associated with RestlessLegs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) usinghigh-frequency electrostimulation. The device can include or be coupledto external electrostimulation electrodes, such as can be configured tobe affixed to a subject such as at a location associated with at leastone of, or at least one branch (e.g., directly connected peripherally ordistally extending branch) of, a sural nerve, a peroneal nerve, or afemoral nerve to deliver electrostimulation thereto. Anelectrostimulation generator circuit can be adapted to be coupled to theelectrostimulation electrodes to generate the electrostimulation fordelivery by the electrostimulation electrodes. A controller circuit canbe coupled to the electrostimulation generator circuit, such as tocontrol at least one parameter of the electrostimulation.

Aspect 36 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-35, such as can include oruse the electrostimulation generator circuit including a subsensory,subthreshold, AC electrostimulation generator circuit, adapted to becoupled to electrostimulation electrodes to deliver electrostimulationat the location at a frequency that exceeds 500 Hz and is less than15,000 Hz to the location such as to help reduce or alleviate the one ormore symptoms associated with RLS or PLMD.

Aspect 37 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-36, such as can include oruse the electrostimulation generator circuit having a controlled currentcircuit such as can be configured to control electrostimulation currentsuch as at a current level that is between 5 milliamperes and 30milliamperes.

Aspect 38 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-37, such as can include oruse the electrostimulation generator circuit being configured to providea controlled current electrostimulation waveform such as having afrequency that is between 4 kHz and 5 kHz.

Aspect 39 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-38, such as can include oruse a stabilizer such as to hold at least a portion of the device at atarget location.

Aspect 40 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-39, such as can include oruse the stabilizer including a skin patch configured to adhere to thesubject at the location for delivering electrostimulations thereto.

Aspect 41 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-40, such as can include oruse a stabilizer including a wearable sleeve that can be configured tohold the device at the location for delivering electrostimulationsthereto.

Aspect 42 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-41, such as can include oruse a user-interface, such as can be coupled to the controller circuitsuch as to trigger or adjust electrostimulation such as in response toat least one of: an RLS or PLMD symptom, a time-of-day, a postureindication, a sleep-status indication, an autonomic balance indication,or a leg or foot movement indication.

Aspect 43 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-42, such as can include oruse a sensor that can be coupled to the controller circuit such as totrigger or adjust electrostimulation such as in response to at least oneof: an RLS or PLMD symptom, a time-of-day, a posture indication, asleep-status indication, an autonomic balance indication, or a leg orfoot movement indication.

Aspect 44 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-43, such as can include oruse an accelerometer such as can be configured to detect movement of atleast a portion of the subject (e.g., leg or foot movement).

Aspect 45 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-44, such as can include oruse the sensor including a clock circuit such as to provide atime-of-day indication.

Aspect 46 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-45, such as can include oruse a posture sensor such as can be configured to detect a posture(e.g., upright, recumbent, or the like) of the subject.

Aspect 47 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-46, such as can include oruse a sleep sensor configured to indicate a sleep status of the subject.

Aspect 48 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-47, such as can include oruse the sensor including an automatic balance indicator such as can beconfigured to provide information about at least one of a sympathetictone or a parasympathetic tone of the subject.

Aspect 49 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-48, such as can include oruse the sensor including an impedance sensor such as can be configuredto provide information about an impedance of or associated with thesubject to the controller circuit such as for adjusting a parameter ofthe electrostimulation in response thereto.

Aspect 50 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-49, such as can include oruse the controller circuit being configured to use information about adrug therapy of the subject such as to initiate or adjust a parameter ofthe electrostimulation.

Aspect 51 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-50, such as can include oruse a transceiver circuit such as can be configured to communicateinformation such as about the delivered electrostimulation, itsefficacy, one or more physiological parameters, or the one or moresymptoms to a local or remote external device.

Aspect 52 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-51, such as can include oruse the electrostimulation electrodes being carried on an adhesivepatch.

Aspect 53 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-52, such as can include oruse the adhesive patch being configured for a single use beforedisposing of the patch.

Aspect 54 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-53, such as can include oruse the device further including electronic circuitry or a battery alsocarried by the adhesive patch.

Aspect 55 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-54, such as can include oruse a device for treating one or more symptoms associated with RestlessLegs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) usingelectrostimulation at a sural nerve location posterior and inferior toan ankle malleolus of a human subject. The device can include or use awearable adhesive patch, including external electrostimulationelectrodes, such as can be configured to be affixed to a subject at thesural nerve location, and such as can include electrical contacts in afirst arrangement for receiving signals from an electrostimulationelectronics unit that is user-attachable and user-detachable from thepatch.

Aspect 56 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-55, such as can include oruse the patch being sized and shaped to fit on a lateral side of a footbetween the ankle malleolus and a heel of the human subject.

Aspect 57 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-56, such as can include oruse the patch including a central lobe for receiving theelectrostimulation electronics unit (and optionally additionallycarrying an electrostimulation electrode), and a plurality of wingsextending from the central lobe such as to carry respectiveelectrostimulation electrodes for contacting skin of the subject.

Aspect 58 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-57, such as can include oruse the electrostimulation electronics unit, such as can includeelectrical contacts in a second arrangement that matches the firstarrangement of the patch.

Aspect 59 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-58, such as can include oruse one or more of the electrical contacts of the patch being magnetizedsuch as to attract similarly arranged contacts of the electrostimulationelectronics unit.

Aspect 60 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-59, such as can include oruse the patch including: a lower layer carrying hydrogel electrodes; anupper layer, including electrical contacts for interfacing with theelectronics unit; and an intermediate layer, providing electricalconnections to the hydrogel electrodes carried by the lower layer and tothe electrical contacts included in the upper layer.

Aspect 61 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-60, such as can include oruse a device for treating one or more symptoms associated with RestlessLegs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) usingelectrostimulation at a peroneal nerve location inferior to a patellaand to a tibial tuberosity on an anterior portion of a lower limb of ahuman subject. The device can include or use a wearable adhesive patch,such as including external electrostimulation electrodes, such as can beconfigured to be affixed to a subject at the peroneal nerve location,and including electrical contacts in a first arrangement such as forreceiving signals from an electrostimulation electronics unit that isuser-attachable and user-detachable from the patch.

Aspect 62 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-61, such as can include oruse a wearable adhesive patch includes electrodes at respective ends ofthe patch for placement on opposing lateral and medial locations acrossthe tibia, and wherein the electrical contacts in the first arrangementare located at one of the ends of the patch.

Aspect 63 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-62, such as can include oruse the wearable adhesive patch including or using a return electrodesuch as can be arranged to be positioned anterior to the tibia when anelectrode at one of the ends of the patch is placed laterally ormedially over a peroneal nerve target.

Aspect 64 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-63, such as can include oruse the patch including lobes extending in opposing directions at eachend of the patch, each lobe carrying an electrode.

Aspect 65 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-64, such as can include oruse the patch including or using: a lower layer carrying hydrogelelectrodes; an upper layer, including electrical contacts forinterfacing with the electronics unit; and an intermediate layer,providing electrical connections to the hydrogel electrodes carried bythe lower layer and to the electrical contacts included in the upperlayer.

Aspect 66 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-65, such as can include oruse a device for treating one or more symptoms associated with RestlessLegs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) usingelectrostimulation at a femoral nerve location anterior to a superiorportion of a femur of a human subject. The device can include or use awearable adhesive patch, including external electrostimulationelectrodes, configured to be affixed to a subject at the peroneal nervelocation, and including electrical contacts in a first arrangement forreceiving signals from an electrostimulation electronics unit that isuser-attachable and user-detachable from the patch.

Aspect 67 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-66, such as can include oruse the wearable adhesive patch including electrodes at respective endsof the patch for placement on opposing lateral and medial locationsacross the femur, and wherein the electrical contacts in the firstarrangement are located at one of the ends of the patch.

Aspect 68 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-67, such as can include oruse the wearable adhesive patch including an return electrode arrangedto be positioned anterior to the femur when an electrode at one of theends of the patch is placed laterally or medially over a femoral nervetarget.

Aspect 69 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-68, such as can include oruse the patch including lobes extending in opposing directions at eachend of the patch, each lobe carrying an electrode.

Aspect 70 can include or use, or can optionally be combined with thesubject matter of one or more of Aspects 1-69, such as can include oruse the patch including: a lower layer carrying hydrogel electrodes; anupper layer, including electrical contacts for interfacing with theelectronics unit; and an intermediate layer, providing electricalconnections to the hydrogel electrodes carried by the lower layer and tothe electrical contacts included in the upper layer.

The above description includes references to the accompanying drawings,which form a part of the detailed description. The drawings show, by wayof illustration, specific embodiments in which the invention can bepracticed. These embodiments are also referred to herein as “aspects” or“examples.” Such examples can include elements in addition to thoseshown or described. However, the present inventors also contemplateexamples in which only those elements shown or described are provided.Moreover, the present inventors also contemplate examples using anycombination or permutation of those elements shown or described (or oneor more aspects thereof), either with respect to a particular example(or one or more aspects thereof), or with respect to other examples (orone or more aspects thereof) shown or described herein.

In the event of inconsistent usages between this document and anydocuments so incorporated by reference, the usage in this documentcontrols.

In this document, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.” In thisdocument, the term “or” is used to refer to a nonexclusive or, such that“A or B” includes “A but not B,” “B but not A,” and “A and B,” unlessotherwise indicated. In this document, the terms “including” and “inwhich” are used as the plain-English equivalents of the respective terms“comprising” and “wherein.” Also, in the following claims, the terms“including” and “comprising” are open-ended, that is, a system, device,article, composition, formulation, or process that includes elements inaddition to those listed after such a term in a claim are still deemedto fall within the scope of that claim. Moreover, in the followingclaims, the terms “first,” “second,” and “third,” etc. are used merelyas labels, and are not intended to impose numerical requirements ontheir objects.

Geometric terms, such as “parallel”, “perpendicular”, “round”, or“square”, are not intended to require absolute mathematical precision,unless the context indicates otherwise. Instead, such geometric termsallow for variations due to manufacturing or equivalent functions. Forexample, if an element is described as “round” or “generally round,” acomponent that is not precisely circular (e.g., one that is slightlyoblong or is a many-sided polygon) is still encompassed by thisdescription.

Method examples described herein can be machine or computer-implementedat least in part. Some examples can include a computer-readable mediumor machine-readable medium encoded with instructions operable toconfigure an electronic device to perform methods as described in theabove examples. An implementation of such methods can include code, suchas microcode, assembly language code, a higher-level language code, orthe like. Such code can include computer readable instructions forperforming various methods. The code may form portions of computerprogram products. Further, in an example, the code can be tangiblystored on one or more volatile, non-transitory, or non-volatile tangiblecomputer-readable media, such as during execution or at other times.Examples of these tangible computer-readable media can include, but arenot limited to, hard disks, removable magnetic disks, removable opticaldisks (e.g., compact disks and digital video disks), magnetic cassettes,memory cards or sticks, random access memories (RAMs), read onlymemories (ROMs), and the like.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or moreaspects thereof) may be used in combination with each other. Otherembodiments can be used, such as by one of ordinary skill in the artupon reviewing the above description. The Abstract is provided to complywith 37 C.F.R. § 1.72(b), to allow the reader to quickly ascertain thenature of the technical disclosure. It is submitted with theunderstanding that it will not be used to interpret or limit the scopeor meaning of the claims. Also, in the above Detailed Description,various features may be grouped together to streamline the disclosure.This should not be interpreted as intending that an unclaimed disclosedfeature is essential to any claim. Rather, inventive subject matter maylie in less than all features of a particular disclosed embodiment.Thus, the following claims are hereby incorporated into the DetailedDescription as examples or embodiments, with each claim standing on itsown as a separate embodiment, and it is contemplated that suchembodiments can be combined with each other in various combinations orpermutations. The scope of the invention should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

The claimed invention is:
 1. A method of treating one or more symptomsassociated with Restless Legs Syndrome (RLS) or Periodic Limb MovementDisorder (PLMD) using applied high-frequency electrostimulation, themethod comprising: locating at least one electrostimulation electrode ata location associated with at least one of, or at least one branch of, asural nerve, a peroneal nerve, or a femoral nerve of a subject with RLSor PLMD; and delivering electrostimulation to the location to helpreduce or alleviate the one or more symptoms associated with RLS orPLMD, wherein the delivering electrostimulation includes deliveringsubsensory, subthreshold electrostimulation to the location using awaveform to target A-Beta fibers for activation to help inhibitoveractive at least one of A-Delta and C fibers.
 2. The method of claim1, wherein the delivering electrostimulation includes deliveringsubsensory, subthreshold, AC high frequency (HF) electrostimulation tothe location at a HF frequency that exceeds 500 Hz and is less than15,000 Hz to help reduce or alleviate the one or more symptomsassociated with RLS or PLMD.
 3. The method of claim 2, wherein thedelivering electrostimulation includes delivering charge-balanced ACcontrolled-current electrostimulation at a controlled current level thatis between 5 milliamperes and 30 milliamperes.
 4. The method of claim 2,wherein the delivering electrostimulation is at a frequency that isbetween 4 kHz and 5 kHz.
 5. The method of claim 1, wherein deliveringelectrostimulation includes delivering controlled-currentelectrostimulation that is established or adjusted based on a measuredload impedance or component thereof.
 6. The method of claim 1, whereindelivering electrostimulation includes using an electrostimulationwaveform providing a resulting measured compound action potential (CAP)having a higher amplitude ratio of A-Beta fiber to C fiber componentsrecorded at a distance from the electrostimulation electrode along anassociated one of a sural nerve, a peroneal nerve, or a femoral nerve,as compared to a reference electrostimulation waveform having afrequency of 150 Hz.
 7. The method of claim 1, wherein the deliveringelectrostimulation is triggered or adjusted automatically at least inpart based on at least one of: a sensor or other indication of an RLS orPLMD symptom of the subject; a sensor or other indication of posture ofthe subject; a sensor or other indication of sleep status or sleep stateof the subject; a sensor or other indication of an autonomic balance ofthe subject; a sensor or other indication of leg or foot movement of thesubject; an indication of a drug therapy of the subject.
 8. The methodof claim 1, further comprising, using information about the deliveredelectrostimulation to influence a drug therapy of the subject.
 9. Themethod of claim 1, further comprising: monitoring at least one of aflexion response or a compound action potential (CAP) response.
 10. Themethod of claim 1, wherein the delivering the electrostimulationproduces a change in a flexion response in a flexor muscle of anipsilateral limb.
 11. The method of claim 1, wherein the locating anelectrostimulation electrode is at an external location associated witha sural nerve or at least one branch thereof.
 12. The method of claim 1,wherein the locating an external electrostimulation electrode is at alocation associated with a peroneal nerve or at least one branchthereof.
 13. The method of claim 1, wherein the locating anelectrostimulation electrode is at an external location associated witha femoral nerve or at least one branch thereof.
 14. The method of claim1, wherein the locating an electrostimulation electrode is at anexternal location at or near a knee of the subject.
 15. The method ofclaim 1, wherein the locating the electrostimulation electrode is at anexternal location at or near a heel of the subject.
 16. The method ofclaim 1, wherein the locating the electrostimulation electrode is at anexternal location at or near a peroneal target below a patella and belowa tibial tuberosity on an anterior portion of the subject's lower limb.17. An external device for treating one or more symptoms associated withRestless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD)using high-frequency electrostimulation, the device comprising: externalelectrostimulation electrodes, configured to be affixed to a subject ata location associated with at least one of, or at least one branch of, asural nerve, a peroneal nerve, or a femoral nerve to deliverelectrostimulation thereto; an electrostimulation generator circuit,adapted to be coupled to the electrostimulation electrodes to generatethe electrostimulation for delivery by the electrostimulationelectrodes; and a controller circuit, coupled to the electrostimulationgenerator circuit, to control at least one parameter of theelectrostimulation, wherein the electrostimulation includes asubsensory, subthreshold electrostimulation for delivery to the locationusing a waveform to target A-Beta fibers for activation to help inhibitoveractive at least one of A-Delta and C fibers.
 18. The device of claim17, wherein the electrostimulation generator circuit includes asubsensory, subthreshold, AC electrostimulation generator circuit,adapted to be coupled to electrostimulation electrodes to deliverelectrostimulation at the location at a frequency that exceeds 500 Hzand is less than 15,000 Hz to the location to help reduce or alleviatethe one or more symptoms associated with RLS or PLMD.
 19. The device ofclaim 17, wherein the electrostimulation generator circuit includes acontrolled current circuit configured to control electrostimulationcurrent at a current level that is between 5 milliamperes and 30milliamperes.
 20. The device of claim 17, wherein the electrostimulationgenerator circuit is configured to provide a controlled currentelectrostimulation waveform having a frequency that is between 4 kHz and5 kHz.
 21. The device of claim 17, further including a stabilizer tohold at least a portion of the device at the location, wherein thestabilizer includes a skin patch configured to adhere to the subject atthe location for delivering electrostimulations thereto.
 22. The deviceof claim 17, including a user-interface, coupled to the controllercircuit to trigger or adjust electrostimulation based at least in parton at least one of: an RLS or PLMD symptom, a time-of-day, a postureindication, a sleep-status indication, an autonomic balance indication,or a leg or foot movement indication.
 23. The device of claim 17,including a sensor coupled to the controller circuit to trigger oradjust electrostimulation based at least in part on at least one of: anRLS or PLMD symptom, a time-of-day, a posture indication, a sleep-statusindication, an autonomic balance indication, or a leg or foot movementindication.
 24. The device of claim 23, wherein the sensor includes anaccelerometer configured to detect at least one of movement or postureof at least a portion of the subject.
 25. The device of claim 17,comprising an impedance sensor configured to provide information aboutan impedance associated with the subject to the controller circuit foradjusting a parameter of the electrostimulation in response thereto. 26.A device for treating one or more symptoms associated with Restless LegsSyndrome (RLS) or Periodic Limb Movement Disorder (PLMD) usingelectrostimulation at a sural nerve location posterior and inferior toan ankle malleolus of a human subject, the device comprising: a wearableadhesive patch, including external electrostimulation electrodes,configured to be affixed to a subject at the sural nerve location, andincluding electrical contacts in a first arrangement for receivingsignals from an electrostimulation electronics unit that isuser-attachable and user-detachable from the patch, theelectrostimulation electrodes configured to deliver a subsensory,subthreshold electrostimulation to the location using a waveform totarget A-Beta fibers for activation to help inhibit overactive at leastone of A-Delta and C fibers.
 27. The device of claim 26, wherein thepatch is sized and shaped to fit on a lateral side of a foot between theankle malleolus and a heel of the human subject, wherein the patchincludes a central lobe for receiving the electrostimulation electronicsunit, and a plurality of wings extending from the central lobe to carryrespective electrostimulation electrodes for contacting skin of thesubject.
 28. A device for treating one or more symptoms associated withRestless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD)using electrostimulation at a peroneal nerve location inferior to apatella and to a tibial tuberosity on an anterior portion of a lowerlimb of a human subject, the device comprising: a wearable adhesivepatch, including external electrostimulation electrodes, configured tobe affixed to a subject at the peroneal nerve location, and includingelectrical contacts in a first arrangement for receiving signals from anelectrostimulation electronics unit that is user-attachable anduser-detachable from the patch, the electrostimulation electrodesconfigured to deliver a subsensory, subthreshold electrostimulation tothe location using a waveform to target A-Beta fibers for activation tohelp inhibit overactive at least one of A-Delta and C fibers.
 29. Thedevice of claim 28, wherein the wearable adhesive patch includeselectrodes at respective ends of the patch for placement on opposinglateral and medial locations across the tibia, and wherein theelectrical contacts in the first arrangement are located at one of theends of the patch.
 30. The device of claim 29, wherein the wearableadhesive patch includes an electrode arranged to be positioned anteriorto the tibia when an electrode at one of the ends of the patch is placedlaterally or medially over a peroneal nerve target.